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USRE44638E1 - Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta - Google Patents

Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta Download PDF

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USRE44638E1
USRE44638E1 US13/730,256 US200513730256A USRE44638E US RE44638 E1 USRE44638 E1 US RE44638E1 US 200513730256 A US200513730256 A US 200513730256A US RE44638 E USRE44638 E US RE44638E
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phenyl
quinazolin
ylamino
purin
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Kerry W. Fowler
Danwen Huang
Edward A. Kesicki
Hua Chee Ooi
Amy Oliver
Fuqiang Ruan
Jennifer Treiberg
Kamal Deep PURI
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Gilead Sciences Inc
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Icos Corp
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Definitions

  • the present invention relates generally to phosphatidylinositol 3-kinase (PI3K) enzymes, and more particularly to selective inhibitors of PI3K activity and methods of using such inhibitors.
  • PI3K phosphatidylinositol 3-kinase
  • PI 3-kinase phosphatidylinositol 3-kinase
  • PI3K originally was identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol 2:358-60 (1992)).
  • PIP3 phosphatidylinositol-3,4,5-triphosphate
  • PI 3-kinase activation is believed to be involved in a range of cellular responses including cell growth, differentiation, and apoptosis (Parker et al., Curr. Biol., 5:577-99 (1995); Yao et al., Science, 267:2003-05 (1995)).
  • PKC protein kinase C
  • Class I PI3Ks can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIP2) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-biphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively.
  • Class II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate
  • Class III PI3Ks can only phosphorylate PI.
  • PI 3-kinase The initial purification and molecular cloning of PI 3-kinase revealed that it was a heterodimer consisting of p85 and p110 subunits (Otsu et al., Cell, 65:91-104 (1991); Hiles et al., Cell, 70:419-29 (1992)). Since then, four distinct Class I PI3Ks have been identified, designated PI3K ⁇ , ⁇ , ⁇ , and ⁇ , each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit.
  • p110 ⁇ interacts with the same regulatory subunit, i.e., p85
  • p110 ⁇ interacts with a distinct p101 regulatory subunit.
  • the patterns of expression of each of these PI3Ks in human cells and tissues also are distinct. Though a wealth of information has been accumulated on the cellular functions of PI 3-kinases in general, the roles played by the individual isoforms are largely unknown.
  • bovine p110 ⁇ Cloning of bovine p110 ⁇ has been described. This protein was identified as related to the Saccharomyces cerevisiae protein: Vps34p, a protein involved in vacuolar protein processing. The recombinant p110 ⁇ product was also shown to associate with p85 ⁇ , to yield a PI3K activity in transfected COS-1 cells. See Hiles et al., Cell, 70, 419-29 (1992).
  • p110 ⁇ The cloning of a second human p110 isoform, designated p110 ⁇ , is described in Hu et al., Mol. Cell. Biol., 13:7677-88 (1993).
  • This isoform is said to associate with p85 in cells, and to be ubiquitously expressed, as p110 ⁇ mRNA has been found in numerous human and mouse tissues, as well as in human umbilical vein endothelial cells, Jurkat human leukemic T cells, 293 human embryonic kidney cells, mouse 3T3 fibroblasts, HeLa cells, and NBT2 rat bladder carcinoma cells.
  • p110 ⁇ isoform is broadly important in signaling pathways.
  • the p85 subunit acts to localize PI 3-kinase to the plasma membrane by the interaction of its SH2 domain with phosphorylated tyrosine residues (present in an appropriate sequence context) in target proteins (Rameh et al., Cell, 83:821-30 (1995)).
  • p85 ⁇ which is ubiquitously expressed
  • p85 ⁇ which is primarily found in the brain and lymphoid tissues
  • association of the p85 subunit to the PI 3-kinase p110 ⁇ , ⁇ , or ⁇ catalytic subunits appears to be required for the catalytic activity and stability of these enzymes.
  • the binding of Ras proteins also upregulates PI 3-kinase activity.
  • p110 ⁇ contains an additional domain termed a “pleckstrin homology domain” near its amino terminus. This domain allows interaction of p110 ⁇ with the ⁇ subunits of heterotrimeric G proteins and this interaction appears to regulate its activity.
  • the p101 regulatory subunit for PI3 Kgamma was originally cloned in swine, and the human ortholog identified subsequently (Krugmann et al., J. Biol. Chem., 274:17152-8 (1999)). Interaction between the N-terminal region of p101 with the N-terminal region of p110 ⁇ appears to be critical for the PI3K ⁇ activation through G ⁇ mentioned above.
  • a constitutively active PI3K polypeptide is described in International Publication No. WO 96/25488.
  • This publication discloses preparation of a chimeric fusion protein in which a 102-residue fragment of p85 known as the inter-SH2 (iSH2) region is fused through a linker region to the N-terminus of murine p110.
  • the p85 iSH2 domain apparently is able to activate PI3K activity in a manner comparable to intact p85 (Klippel et al., Mol. Cell. Biol., 14:2675-85 (1994)).
  • PI 3-kinases can be defined by their amino acid identity or by their activity. Additional members of this growing gene family include more distantly related lipid and protein kinases including Vps34 TOR1, TOR2 of Saccharomyces cerevisiae (and their mammalian homologs such as FRAP and mTOR), the ataxia telangiectasia gene product (ATR), and the catalytic subunit of DNA-dependent protein kinase (DNA-PK). See generally, Hunter, Cell, 83:1-4 (1995).
  • PI 3-kinase also appears to be involved in a number of aspects of leukocyte activation.
  • a p85-associated PI 3-kinase activity has been shown to physically associate with the cytoplasmic domain of CD28, which is an important costimulatory molecule for the activation of T-cells in response to antigen (Pages et al., Nature, 369:327-29 (1994); Rudd, Immunity, 4:527-34 (1996)).
  • Activation of T cells through CD28 lowers the threshold for activation by antigen and increases the magnitude and duration of the proliferative response.
  • interleukin-2 IL2
  • T cell growth factor an important T cell growth factor
  • PI 3-kinase inhibitors Two compounds, LY294002 and wortmannin, have been widely used as PI 3-kinase inhibitors. These compounds, however, are nonspecific PI3K inhibitors, as they do not distinguish among the four members of Class I PI 3-kinases.
  • the IC 50 values of wortmannin against each of the various Class I PI 3-kinases are in the range of 1-10 nM.
  • the IC 50 values for LY294002 against each of these PI 3-kinases is about 1 ⁇ M (Fruman et al., Ann. Rev. Biochem., 67:481-507 (1998)). Hence, the utility of these compounds in studying the roles of individual Class I PI 3-kinases is limited.
  • PI3K ⁇ polypeptide
  • a need also exists for functional characterization of PI3K ⁇ .
  • understanding of PI3K ⁇ requires further elaboration of the structural interactions of p110 ⁇ , both with its regulatory subunit and with other proteins in the cell.
  • a need also remains for selective or specific inhibitors of PI3K isozymes, such that the functions of each isozyme can be better characterized.
  • selective or specific inhibitors of PI3K ⁇ are desirable for exploring the role of this isozyme and for development of pharmaceuticals to modulate activity of the isozyme.
  • One aspect of the present invention is to provide compounds capable of inhibiting the biological activity of human PI3K ⁇ . Another aspect of the present invention is to provide compounds that inhibit PI3K ⁇ selectively compared to the other PI3K isoforms. Still another aspect of the invention is to provide a method of selectively modulating human PI3K ⁇ activity, and thereby promote medical treatment of diseases mediated by PI3K ⁇ dysfunction. Yet another aspect of the invention is to provide a method of characterizing the function of human PI3K ⁇ .
  • Another aspect of the present invention is to provide a method of disrupting leukocyte function comprising contacting leukocytes with a compound that selectively inhibits phosphatidylinositol 3-kinase delta (PI3K ⁇ ) activity in the leukocytes.
  • the leukocytes can comprise cells selected from the group consisting of neutrophils, B lymphocytes, T lymphocytes, and basophils.
  • the method comprises disrupting at least one neutrophil function selected from the group consisting of stimulated superoxide release, stimulated exocytosis, and chemotactic migration.
  • the method does not substantially disrupt bacterial phagocytosis or bacterial killing by the neutrophils.
  • the leukocytes comprise B lymphocytes
  • the method comprises disrupting proliferation of the B lymphocytes or antibody production by the B lymphocytes.
  • the leukocytes comprise T lymphocytes
  • the method comprises disrupting proliferation of the T lymphocytes.
  • the leukocytes comprise basophils
  • the method comprises disrupting histamine release by the basophils.
  • the PI3K ⁇ inhibitor is selective. It is preferred that the PI3K ⁇ inhibitor is at least about 100-fold selective for inhibition of p110 ⁇ relative to p110 ⁇ , at least about 40-fold selective relative to p110 ⁇ , and at least about 10-fold selective relative to p110 ⁇ in a biochemical assay.
  • Compounds of the present invention are capable of inhibiting PI3K ⁇ activity and have a structural formula (I):
  • X and Y independently, are N or CR c ;
  • Z is N—R 7 or O
  • R 1 are the same and are hydrogen, halo, or C 1-3 alkyl
  • R 2 and R 3 independently, are hydrogen, halo, or C 1-3 alkyl
  • R 4 is hydrogen, halo, OR a , CN, C 2-6 alkynyl, C( ⁇ O)R a , C( ⁇ O)NR a R b , C 3-6 heterocycloalkyl, C 1-3 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyleneOR a , OC 1-3 alkyleneNR a R b , OC 1-3 alkyleneC 3-6 cycloalkyl, OC 3-6 heterocycloalkyl, OC 1-3 alkyleneC ⁇ CH, or OC 1-3 alkyleneC( ⁇ O)NR a R b ;
  • R 5 is C 1-3 alkyl, CH 2 CF 3 , phenyl, CH 2 C ⁇ CH, C 1-3 alkyleneOR e , C 1-4 alkyleneNR a R b , or C 1-4 alkyleneNHC( ⁇ O)OR a ,
  • R 6 is hydrogen, halo, or NR a R b ;
  • R 7 is hydrogen or R 5 and R 7 are taken together with the atoms to which they are attached to form a five- or six-membered saturated ring;
  • R 8 is C 1-3 alkyl, halo, CF 3 , or CH 2 C 3-6 heterocycloalkyl
  • n 0, 1, or 2;
  • R a is hydrogen, C 1-4 alkyl, or CH 2 C 6 H 5 ;
  • R b is hydrogen or C 1-3 alkyl
  • R c is hydrogen, C 1-3 alkyl, or halo
  • R 1 groups are different from hydrogen, R 2 and R 4 are the same;
  • Another aspect of the present invention is to provide compounds of structural formula (II) and capable of inhibiting PI3K ⁇ activity:
  • Another aspect of the present invention is to provide a method of treating a medical condition mediated by neutrophils comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of structural formulae (I) or (II).
  • exemplary medical conditions that can be treated according to the method include those conditions characterized by an undesirable neutrophil function selected from the group consisting of stimulated superoxide release, stimulated exocytosis, and chemotactic migration.
  • phagocytic activity or bacterial killing by neutrophils is substantially uninhibited.
  • Still another aspect of the present invention is to provide a method of disrupting a function of osteoclasts comprising contacting osteoclasts with a compound of structural formulae (I) or (II).
  • Another aspect of the present invention is to provide a method of ameliorating a bone-resorption disorder in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of structural formulae (I) or (II).
  • a preferred bone-resorption disorder amenable to treatment according to the method is osteoporosis.
  • Yet another aspect of the present invention is to provide a method of inhibiting the growth or proliferation of cancer cells of hematopoietic origin comprising contacting the cancer cells with a compound of structural formulae (I) or (II).
  • the method can be advantageous in inhibiting the growth or proliferation of cancers selected from the group consisting of lymphomas, multiple myelomas, and leukemias.
  • Another aspect of the present invention is to provide a method of inhibiting kinase activity of a PI3K ⁇ polypeptide comprising contacting the PI3K ⁇ polypeptide with a compound of structural formulae (I) or (II).
  • Still another aspect of the present invention is to provide a method of disrupting leukocyte function comprising contacting leukocytes with a compound of structural formulae (I) or (II).
  • Another aspect of the present invention is to provide compounds of structural formulae (I) or (II) that inhibit PI3K ⁇ activity in biochemical and cell-based assays, and exhibit a therapeutic benefit in treating medical conditions wherein PI3K ⁇ activity is excessive or undesirable.
  • Another aspect of the present invention is to provide pharmaceutical compositions comprising one or more compounds of structural formulae (I) or (II), and use of the compositions in a therapeutic treatment, wherein inhibition of the PI3K ⁇ polypeptide, in vivo or ex vivo, provides a therapeutic benefit or is of research or diagnostic interest.
  • Another aspect of the present invention is to provide an article of manufacture for human pharmaceutical use comprising:
  • a container optionally further comprising a package insert providing that the composition is useful in the treatment of a disease or disorder mediated by PI3K ⁇ activity.
  • Another aspect of the present invention is to provide:
  • a container optionally further comprising a package insert providing that the composition is useful in the treatment of a bone-resorption disorder or a cancer of a hematopoietic origin.
  • the present invention provides compounds that selectively inhibit the activity of PI3K ⁇ .
  • the present invention further provides methods of using the compounds for inhibiting PI3K ⁇ activity, including methods of selectively modulating the activity of the PI3 ⁇ isozyme in cells, especially leukocytes, osteoclasts, and cancer cells.
  • the methods include in vitro, in vivo, and ex vivo applications.
  • the invention provides pharmaceutical compositions comprising a selective PI3K ⁇ inhibitor of structural formulae (I) or (II). Also provided are articles of manufacture comprising a selective PI3K ⁇ inhibitor compound (or a pharmaceutical composition comprising the compound) and instructions for using the compound. Other methods of the invention include enabling the further characterization of the physiological role of the isozyme.
  • the methods described herein benefit from the use of compounds that selectively inhibit, and preferably specifically inhibit, the activity of PI3K ⁇ in cells, including cells in vitro, in vivo, or ex vivo.
  • Cells treated by methods of the present invention include those that express endogenous PI3K ⁇ , wherein endogenous indicates that the cells express PI3K ⁇ absent recombinant introduction into the cells of one or more polynucleotides encoding a PI3K ⁇ polypeptide or a biologically active fragment thereof.
  • the present methods also encompass use of cells that express exogenous PI3K ⁇ , wherein one or more polynucleotides encoding PI3K ⁇ or a biologically active fragment thereof have been introduced into the cell using recombinant procedures.
  • the cells can be in vivo, i.e., in a living subject, e.g., a mammal, including humans, wherein a PI3K ⁇ inhibitor can be used therapeutically to inhibit PI3K ⁇ activity in the subject.
  • the cells can be isolated as discrete cells or in a tissue, for ex vivo or in vitro methods.
  • In vitro methods encompassed by the invention can comprise the step of contacting a PI3K ⁇ enzyme or a biologically active fragment thereof with an inhibitor compound of the invention.
  • the PI3K ⁇ enzyme can include a purified and isolated enzyme, wherein the enzyme is isolated from a natural source (e.g., cells or tissues that normally express a PI3K ⁇ polypeptide absent modification by recombinant technology) or isolated from cells modified by recombinant techniques to express exogenous enzyme.
  • a natural source e.g., cells or tissues that normally express a PI3K ⁇ polypeptide absent modification by recombinant technology
  • isolated from cells modified by recombinant techniques to express exogenous enzyme e.g., cells or tissues that normally express a PI3K ⁇ polypeptide absent modification by recombinant technology
  • Potency typically is expressed as the concentration of a compound required to achieve a certain result. The greater the potency, the less compound required to perform its intended function.
  • In vitro potency typically is expressed in terms of IC 50 values measured using a dose-response assay. IC 50 values can be measured by contacting a sensitive assay system with a compound of interest over a range of concentrations, including concentrations at which no or minimal effect is observed, through higher concentrations at which partial effect is observed, to saturating concentrations at which a maximum effect is observed.
  • such assays of the dose-response effect of inhibitor compounds can be described as a sigmoidal curve expressing a degree of inhibition as a function of concentration when plotted on a log scale.
  • the curve also theoretically passes through a point at which the concentration is sufficient to reduce activity of the p110 ⁇ enzyme to a level that is 50% that of the difference between minimal and maximal enzyme activity observed in the assay. This concentration is defined as the Inhibitory Concentration at 50% inhibition or IC 50 value.
  • IC 50 values can be determined using either conventional biochemical (acellular) assay techniques or cell-based assay techniques well known to those of ordinary skill in the art.
  • An example of such an assay is provided in the examples below.
  • IC 50 values are obtained by performing the relevant assay at least twice, with the IC 50 value expressed as the average (arithmetic means, or “mean”) of the individual values obtained. More preferably, the assay is repeated from 3 to 10 (or more) times, with the IC 50 value expressed as the mean of the values obtained. Still more preferably, the assay is performed a number of times sufficient to generate a statistically reliable mean IC 50 value, using statistical methods known to those of ordinary skill in the art.
  • compounds of formulae (I) and (II) exhibit unexpectedly low IC 50 values relative to PI3K ⁇ , corresponding to unexpectedly high in vitro potency.
  • compounds of formulae (I) and (II) when assayed as described in Example 14 below, exhibit PI3K ⁇ IC 50 values of less than about 250 nM, less than about 200 nM, less than about 150 nM, less than about 125 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, and in others less than about 5 nM.
  • the compounds of the invention exhibit IC 50 values from about 0.1 nM to about 5 nM.
  • the compounds of formulae (I) and (II) are selective PI3K ⁇ inhibitors.
  • selective PI3K ⁇ inhibitor refers to a compound that inhibits the PI3K ⁇ isozyme more effectively than other isozymes of the PI3K family.
  • a “selective PI3K ⁇ inhibitor” compound is understood to be more selective for PI3K ⁇ than compounds conventionally and generically designated PI3K inhibitors, e.g., wortmannin or LY294002.
  • wortmannin and LY294002 are deemed “nonselective PI3K inhibitors.”
  • compounds of the present invention selectively negatively regulate PI3K ⁇ expression or activity and possess acceptable pharmacological properties for use in the therapeutic methods of the invention.
  • a selective inhibitor alternatively can be understood to refer to at least one compound that exhibits a 50% inhibitory concentration (IC 50 ) with respect to PI3K ⁇ that is at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, at least about 250-fold, at least about 300-fold, at least about 350-fold, at least about 400-fold, at least about 500-fold, at least about 600-fold, at least about 700-fold, at least about 800-fold, at least about 900-fold, or at least about 1000-fold lower than the IC 50 value for PI3K ⁇ .
  • IC 50 50% inhibitory concentration
  • the term selective inhibitor can be understood to refer to at least one compound that exhibits an IC 50 with respect to PI3K ⁇ that is at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 60-fold, at least about 70-fold, at least about 80-fold, at least about 90-fold, or at least about 100-fold lower than the IC 50 for PI3K ⁇ .
  • the term selective inhibitor can be understood to refer to at least one compound that exhibits an IC 50 with respect to PI3K ⁇ that is at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 125-fold, at least about 150-fold, at least about 175-fold, at least about 200-fold, at least about 250-fold, at least about 300-fold, or at least about 350-fold lower than the IC 50 for PI3K ⁇ .
  • the selective inhibitors are typically administered in an amount such that they selectively inhibit PI3K ⁇ , as described above.
  • the most preferred compounds of the present invention therefore, have a low IC 50 value vs. PI3K ⁇ (i.e., the compound is a potent inhibitor), and are selective with respect to inhibiting PI3K ⁇ relative to at least one of PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ .
  • In vivo means within a living subject, as within an animal or human.
  • agents can be used therapeutically in vivo to retard or eliminate the proliferation of aberrantly replicating cells.
  • the agents also can be used in vivo as a prophylactic to prevent aberrant cell proliferation or the manifestation of symptoms associated therewith.
  • Ex vivo means outside a living subject.
  • ex vivo cell populations include cell cultures and biological samples such as fluid or tissue samples from humans or animals. Such samples can be obtained by methods well known in the art.
  • Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, saliva.
  • Exemplary tissue samples include tumors and biopsies. In this context, the present compounds can be in numerous applications, both therapeutic and experimental.
  • tainer means any receptacle and closure therefor suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • package insert means information accompanying the product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, or patient to make an informed decision regarding use of the product.
  • the approving authority may specify the content of the package insert, and such a package insert may be referred to informally as the “label” for the product. as the “label” for the product.
  • the present invention provides a method of inhibiting leukocyte function. More particularly, the present invention provides methods of inhibiting or suppressing functions of neutrophils and T and B lymphocytes.
  • inhibition of PI3K ⁇ activity inhibits functions of neutrophils.
  • the compounds of the present invention elicit inhibition of classical neutrophil functions, such as stimulated superoxide production, stimulated exocytosis, and chemotactic migration.
  • a method of the present invention permits suppression of certain functions of neutrophils, while not substantially affecting other functions of these cells. For example, it has been observed that phagocytosis of bacteria by neutrophils is not substantially inhibited by the selective PI3K ⁇ inhibitor compounds of the present invention.
  • the present invention includes methods of inhibiting neutrophil functions, without substantially inhibiting phagocytosis of bacteria.
  • Neutrophil functions suitable for inhibition according to the present method include any function mediated by PI3K ⁇ activity or expression. Such functions include, without limitation, stimulated superoxide release, stimulated exocytosis or degranulation, chemotactic migration, adhesion to vascular endothelium (e.g., tethering/rolling of neutrophils, triggering of neutrophil activity, and/or latching of neutrophils to endothelium), transmural diapedesis, or emigration through the endothelium to peripheral tissues.
  • these functions can be collectively termed “inflammatory functions,” as they are typically related to neutrophil response to inflammation.
  • the inflammatory functions of neutrophils can be distinguished from the bacterial killing functions exhibited by these cells, e.g., phagocytosis and killing of bacteria. Accordingly, the present invention further includes methods of treating disease states in which one or more of the inflammatory functions of neutrophils are abnormal or undesirable.
  • the compounds of the present invention may be used to inhibit an endogenous immune response stimulated by at least one endogenous factor without substantially inhibiting an exogenous immune response stimulated by at least one exogenous factor as disclosed in US 2005/0043239 A1, which is incorporated herein by reference.
  • the compounds of the present invention may also be used to inhibit an endogenous immune response stimulated by at least one endogenous factor without substantially inhibiting immune responsiveness, as disclosed in US 2005/0043239 A1. Accordingly, the compounds of the invention advantageously permit treatment of conditions associated with an undesirable endogenous immune response stimulated by at least one endogenous factor without compromising the ability to fight infection.
  • the compounds of the present invention may also be used to inhibit leukocyte accumulation as disclosed in US 2005/0054614 A1.
  • the compounds may also be used to inhibit leukocyte tethering to endothelial cells and to inhibit leukocyte transmigration into inflamed tissue, as disclosed in US 2005/0043239 A1. Accordingly, the compounds of the invention advantageously permit treatment of individuals having an inflammatory condition where leukocytes are found to be accumulating at the site of insult or inflamed tissue.
  • PI3K ⁇ plays a role in the stimulated proliferation of lymphocytes, including B cells and T cells. Moreover, PI3K ⁇ appears to play a role in stimulated secretion of antibodies by B cells. Selective PI3K ⁇ inhibitor compounds of the present invention have been employed to establish that these phenomena can be abrogated by inhibition of PI3K ⁇ .
  • the present invention includes methods of using compounds of structural formulae (I) or (II) for inhibiting lymphocyte proliferation, or for inhibiting antibody production by B lymphocytes. Other methods enabled by the present invention include methods of treating disease states in which one or more of these lymphocyte functions are abnormal or undesirable.
  • the methods of this invention can be practiced using compounds of structural formulae (I) or (II).
  • the methods can be practiced using a racemic mixture of the compounds or a specific enantiomer.
  • the S-enantiomer of the compounds are utilized in the present methods.
  • Exemplary compounds include 5-methyl-3-phenyl-2-[1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one; 2-[1-(2-fluoro-9H-purin-6-ylamino)-ethyl]-5-methyl-3-phenyl-3H-quinazolin-4-one; 3-(2,6-difluoro-phenyl)-5-methyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one; 2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(2,6-difluoro-phenyl)-5-methyl-3H-quinazolin-4-one; 3-(2,6-difluoro-phenyl)-2-[1-(2-fluoro-9H-purin-6-ylamino)-ethyl]-3-(2,6-
  • the methods of the invention can be practiced using compounds that exhibit PI3K ⁇ inhibitory activity.
  • the methods of the invention can be practiced using compounds having the general structural formula (I):
  • X and Y independently, are N or CRC
  • Z is N—R 7 or O
  • R 1 are the same and are hydrogen, halo, or C 1-3 alkyl
  • R 2 and R 3 independently, are hydrogen, halo, or C 1-3 alkyl
  • R 4 is hydrogen, halo, OR a , CN, C 2-6 alkynyl, C( ⁇ O)R a , C( ⁇ O)NR a R b , C 3-6 heterocycloalkyl, C 1-3 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyleneOR a , OC 1-3 alkyleneNR a R b , OC 1-3 alkyleneC 3-6 cycloalkyl, OC 3-6 heterocycloalkyl, OC 1-3 alkyleneC ⁇ CH, or OC 1-3 alkyleneC( ⁇ O)NR a R b ;
  • R 5 is C 1-3 alkyl, CH 2 CF 3 , phenyl, CH 2 C ⁇ CH, C 1-3 alkyleneOR e , C 1-4 alkyleneNR a R b , or C 1-4 alkyleneNHC( ⁇ O)OR a ,
  • R 6 is hydrogen, halo, or NR a R b ;
  • R 7 is hydrogen or R 5 and R 7 are taken together with the atoms to which they are attached to form a five- or six-membered saturated ring;
  • R 8 is C 1-3 alkyl, halo, CF 3 , or CH 2 C 3-6 heterocycloalkyl
  • n 0, 1, or 2;
  • R a is hydrogen, C 1-4 alkyl, or CH 2 C 6 H 5 ;
  • R b is hydrogen or C 1-3 alkyl
  • R c is hydrogen, C 1-3 alkyl, or halo
  • R 1 groups are different from hydrogen, R 2 and R 4 are the same;
  • Compounds of the present invention are selective inhibitors of PI3K ⁇ activity.
  • the compounds exhibit inhibition of PI3K ⁇ in biochemical assays, and selectively disrupt function of PI3K ⁇ -expressing cells in cell-based assays.
  • the present compounds have demonstrated an ability to inhibit certain functions in neutrophils and other leukocytes, as well as functions of osteoclasts.
  • compounds of the present invention have the general structural formulae (I) or (II), or a pharmaceutically acceptable salt thereof, or prodrug, or solvate thereof:
  • R 8 is C 1-3 alkyl, F, Cl, or CF 3 .
  • n is 0 (such that there is no R 8 substituent).
  • X and Y independently, are N or CH. In further embodiment exhibiting increased potency, X is N and Y is CH. Alternatively, X and Y may also both be CH. In further embodiments exhibiting increased potency, R 6 is hydrogen, halo, or NH 2 .
  • R 2 and R 4 may differ provided that R 1 is H.
  • R 1 is H
  • free rotation is unexpectedly permitted about the bond connecting the phenyl ring substituent to the quinazoline ring, and the compounds advantageously do not exhibit atropisomerism (i.e., multiple diasteromer formation is avoided).
  • R 2 and R 4 can be the same such that the compounds advantageously do not exhibit atropisomerism.
  • alkyl is defined as straight chained and branched hydrocarbon groups containing the indicated number of carbon atoms, e.g., methyl, ethyl, and straight chain and branched propyl and butyl groups.
  • C 1-3 alkylene and C 1-4 alkylene are defined as hydrocarbon groups containing the indicated number of carbon atoms and one less hydrogen than the corresponding alkyl group.
  • C 2-6 alkynyl is defined as a hydrocarbon group containing the indicated number of carbon atoms and a carbon-carbon triple bond.
  • C 3-6 cycloalkyl is defined as a cyclic hydrocarbon group containing the indicated number of carbon atoms.
  • C 2-6 heterocycloalkyl is defined similarly as cycloalkyl except the ring contains one or two heteroatoms selected from the group consisting of O, NR a , and S.
  • halo is defined as fluoro, bromo, chloro, and iodo.
  • Z is N—R 7
  • the bicyclic ring system containing X and Y is
  • R 1 is hydrogen, fluoro, chloro, methyl, or
  • R 2 is hydrogen, methyl, chloro, or fluoro
  • R 3 is hydrogen or fluoro
  • R 6 is NH 2 , hydrogen, or fluoro
  • R 7 is hydrogen or R 5 and R 7 are taken together to form
  • R 8 is methyl, trifluoromethyl, chloro, or fluoro;
  • R 4 is hydrogen, fluoro, chloro, OH, OCH 3 , OCH 2 C ⁇ CH, O(CH 2 ) 2 N (CH 3 ) 2 , C( ⁇ O)CH 3 , C ⁇ CH, CN, C( ⁇ O)NH 2 , OCH 2 C ( ⁇ O)NH 2 , O(CH 2 ) 2 OCH 3 , O(CH 2 ) 2 N(CH 3 ) 2 ,
  • R 5 is methyl, ethyl, propyl, phenyl, CH 2 OH, CH 2 OCH 2 C 6 H 5 , CH 2 CF 3 , CH 2 OC(CH 3 ) 3 , CH 2 C ⁇ CH, (CH 2 ) 3 N(C 2 H 5 ) 2 , (CH 2 ) 3 NH 2 , (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC (—O)OCH 2 C 6 H 5 , or (CH 2 ) 4 NHC(—O)OCH 2 C 6 H 5 ;
  • R c is hydrogen, methyl, fluoro, or bromo; and n is 0 or 1.
  • the compounds of the present invention include all possible stereoisomers and geometric isomers of compounds of structural formula (I), and include not only racemic compounds, but also the optically active isomers as well.
  • a compound of the present invention is the S-enantiomer of a compound (I), as depicted in structural formula (II).
  • a compound of structural formula (I) When a compound of structural formula (I) is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent. For example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883-88 (1997). Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. Specific stereoisomers, in particular, S-enantiomers of the compounds of the invention, exhibit an excellent ability to inhibit kinase activity of PI3K ⁇ .
  • prodrug refers to compounds that are rapidly transformed in vivo to a compound having structural formulae (I) or (II), for example, by hydrolysis. Prodrug design is discussed generally in Hardma et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-6 (1996). A thorough discussion of prodrugs is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), “Bioreversible Carriers in Drug Design,” American Pharmaceutical Association and Pergamon Press (1987).
  • a biotransformation process can lead to a metabolic by-product, which is itself more active or equally active as compared to the drug initially administered.
  • Increased understanding of these biotransformation processes permits the design of so-called “prodrugs,” which, following a biotransformation, become more physiologically active in their altered state. Prodrugs, therefore, encompass pharmacologically inactive compounds that are converted to biologically active metabolites.
  • prodrugs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product.
  • Prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life.
  • prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate.
  • the resulting conjugate can be inactivated and excreted in the urine, or rendered more potent than the parent compound.
  • High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into the circulation, thereby effectively increasing the biological half-life of the originally administered compound.
  • the PI3K ⁇ protein as well as fragments thereof possessing biological activity, can be used for screening putative inhibitor compounds in any of a variety of drug screening techniques.
  • a inhibitor of PI3K ⁇ is a compound that diminishes or abolishes the ability of PI3K ⁇ to perform any of its biological functions.
  • An example of such compounds is an agent that decreases the ability of a PI3K ⁇ polypeptide to phosphorylate phosphatidylinositol or to target appropriate structures within a cell.
  • the selectivity of a compound that negatively regulates PI3K ⁇ activity can be evaluated by comparing its activity on the PI3K ⁇ to its activity on other proteins.
  • Selective inhibitors include, for example, antibodies and other proteins or peptides that specifically bind to a PI3K ⁇ polypeptide, oligonucleotides that specifically bind to PI3K ⁇ polypeptides, and other nonpeptide compounds (e.g., isolated or synthetic organic molecules) that specifically interact with PI3K ⁇ polypeptides. Inhibitors also include compounds as described above, but which interact with a specific binding partner of PI3K ⁇ polypeptides.
  • cytoplasmic regions of PI3K ⁇ polypeptides that contact other proteins and/or localize PI3K ⁇ within a cell
  • one target for development of modulators is the identified regulatory interaction of p85 with p110 ⁇ , which can be involved in activation and/or subcellular localization of the p110 ⁇ moiety.
  • Still other selective modulators include those that recognize specific regulatory or PI3K ⁇ -encoding nucleotide sequences. Modulators of PI3K ⁇ activity can be therapeutically useful in treatment of a wide range of diseases and physiological conditions in which aberrant PI3K ⁇ activity is involved.
  • the invention provides methods of characterizing the potency of a test compound as an inhibitor of PI3K ⁇ polypeptide, said method comprising the steps of (a) measuring activity of a PI3K ⁇ polypeptide in the presence of a test compound; (b) comparing the activity of the PI3K ⁇ polypeptide in the presence of the test compound to the activity of the PI3K ⁇ polypeptide in the presence of an equivalent amount of a reference compound (e.g., a compound having a known potency against PI3K ⁇ ), wherein a lower activity of the PI3K ⁇ polypeptide in the presence of the test compound than in the presence of the reference indicates that the test compound is a more potent inhibitor than the reference compound, and a higher activity of the PI3K ⁇ polypeptide in the presence of the test compound than in the presence of the reference indicates that the test compound is a less potent inhibitor than the reference compound.
  • a reference compound e.g., a compound having a known potency against PI3K ⁇
  • the invention further provides methods of characterizing the potency of a test compound as an inhibitor of PI3K ⁇ polypeptide, comprising the steps of (a) determining an amount of a reference compound (e.g., a PI3K ⁇ inhibitor compound of the present invention) that inhibits an activity of a PI3K ⁇ polypeptide by a reference percentage of inhibition, thereby defining a reference inhibitory amount for the reference compound; (b) determining an amount of a test compound that inhibits an activity of a PI3K ⁇ polypeptide by a reference percentage of inhibition, thereby defining a reference inhibitory amount for the test compound; (c) comparing the reference inhibitory amount for the test compound to the reference inhibitory amount for the reference compound, wherein a lower reference inhibitory amount for the test compound than for the reference compound indicates that the test compound is a more potent inhibitor than the reference compound, and a higher reference inhibitory amount for the test compound than for the reference compound indicates that the test compound is a less potent inhibitor than the reference compound.
  • the method uses a reference inhibitory amount which is the amount of the compound than inhibits the activity of the PI3K ⁇ polypeptide by 50%, 60%, 70%, or 80%. In another aspect, the method employs a reference inhibitory amount that is the amount of the compound that inhibits the activity of the PI3K ⁇ polypeptide by 90%, 95%, or 99%. These methods comprise determining the reference inhibitory amount of the compounds in an in vitro biochemical assay, in an in vitro cell-based assay, or in an in vivo assay.
  • the invention further provides methods of identifying a inhibitor of PI3K ⁇ activity, comprising the steps of (i) measuring activity of a PI3K ⁇ polypeptide in the presence and absence of a test compound, and (ii) identifying as a inhibitor a test compound that decreases PI3K ⁇ activity and that competes with a compound of the invention for binding to PI3K ⁇ .
  • the invention provides methods for identifying compounds that inhibit PI3K ⁇ activity, comprising the steps of (i) contacting a PI3K ⁇ polypeptide with a compound of the present invention in the presence and absence of a test compound, and (ii) identifying a test compound as a inhibitor of PI3K ⁇ activity wherein the compound competes with a compound of the invention for binding to PI3K ⁇ .
  • the invention therefore provides a method for screening for candidate inhibitors of PI3K ⁇ activity and/or to confirm the mode of action of candidate such inhibitors. Such methods can be employed against other PI3K isoforms in parallel to establish comparative activity of the test compound across the isoforms and/or relative to a compound of the invention.
  • the PI3K ⁇ polypeptide can be a fragment of p110 ⁇ that exhibits kinase activity, i.e., a fragment comprising the catalytic site of p110 ⁇ .
  • the PI3K ⁇ polypeptide can be a fragment from the p110 ⁇ -binding domain of p85 and provides a method to identify allosteric modulators of PI3K ⁇ .
  • the methods can be employed in cells expressing cells expressing PI3K ⁇ or its subunits, either endogenously or exogenously. Accordingly, the polypeptide employed in such methods can be free in solution, affixed to a solid support, modified to be displayed on a cell surface, or located intracellularly. The modulation of activity or the formation of binding complexes between the PI3K ⁇ polypeptide and the agent being tested then can be measured.
  • Human PI3K polypeptides are amenable to biochemical or cell-based high throughput screening (HTS) assays according to methods known and practiced in the art, including melanophore assay systems to investigate receptor-ligand interactions, yeast-based assay systems, and mammalian cell expression systems.
  • HTS high throughput screening
  • HTS assays are used to screen libraries of compounds to identify particular compounds that exhibit a desired property.
  • Any library of compounds can be used, including chemical libraries, natural product libraries, and combinatorial libraries comprising random or designed oligopeptides, oligonucleotides, or other organic compounds.
  • Chemical libraries can contain known compounds, proprietary structural analogs of known compounds, or compounds that are identified from natural product screening.
  • Natural product libraries are collections of materials isolated from naturals sources, typically, microorganisms, animals, plants, or marine organisms. Natural products are isolated from their sources by fermentation of microorganisms followed by isolation and extraction of the fermentation broths or by direct extraction from the microorganisms or tissues (plants or animal) themselves. Natural product libraries include polyketides, nonribosomal peptides, and variants (including nonnaturally occurring variants) thereof. For a review, see Cane et al., Science, 282:63-68 (1998).
  • Combinatorial libraries are composed of large numbers of related compounds, such as peptides, oligonucleotides, or other organic compounds as a mixture. Such compounds are relatively straightforward to design and prepare by traditional automated synthesis protocols, PCR, cloning, or proprietary synthetic methods. Of particular interest are peptide and oligonucleotide combinatorial libraries.
  • Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries.
  • combinatorial chemistry and libraries created thereby see Myers, Curr Opin Biotechnol, 8:701-07 (1997).
  • the invention provides a method for selectively or specifically inhibiting PI3K ⁇ activity therapeutically or prophylactically using compounds of the invention.
  • the method comprises administering a selective or specific inhibitor of PI3K ⁇ activity to an individual in need thereof in an amount sufficient to inhibit PI3K ⁇ activity.
  • the method can be employed to treat humans or animals suffering from, or subject to, a condition whose symptoms or pathology is mediated by PI3K ⁇ expression or activity.
  • Treating refers to preventing a disorder from occurring in an animal that can be predisposed to the disorder, but has not yet been diagnosed as having it; inhibiting the disorder, i.e., arresting its development; relieving the disorder, i.e., causing its regression; or ameliorating the disorder, i.e., reducing the severity of symptoms associated with the disorder.
  • disorder is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
  • the methods of the invention embrace various modes of treating an animal subject, preferably a mammal, more preferably a primate, and still more preferably a human.
  • mammalian animals that can be treated are, for example, humans; companion animals (pets), including dogs and cats; farm animals, including cattle, horses, sheep, pigs, and goats; laboratory animals, including rats, mice, rabbits, guinea pigs, and nonhuman primates; and zoo specimens.
  • Nonmammalian animals include, for example, birds, fish, reptiles, and amphibians.
  • a method of the present invention can be employed to treat subjects, therapeutically or prophylactically, suffering from, or subject to, an inflammatory disorder.
  • One aspect of the present invention derives from the involvement of PI3K ⁇ in mediating aspects of the inflammatory process. Without intending to be bound by any theory, it is theorized that, because inflammation involves processes typically mediated by leukocyte (e.g., neutrophils or lymphocyte) activation and chemotactic transmigration, and because PI3K ⁇ can mediate such phenomena, antagonists of PI3K ⁇ can be used to suppress injury associated with inflammation.
  • leukocyte e.g., neutrophils or lymphocyte
  • Inflammatory disorder can refer to any disease, disorder, or syndrome in which an excessive or unregulated inflammatory response leads to excessive inflammatory symptoms, host tissue damage, or loss of tissue function. “Inflammatory disorder” also refers to a pathological state mediated by influx of leukocytes and/or neutrophil chemotaxis.
  • Inflammation refers to a localized, protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. Inflammation is associated with an influx of leukocytes and/or neutrophil chemotaxis. Inflammation can result from infection with pathogenic organisms and viruses, and from noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune response to foreign antigen, and autoimmune responses. Accordingly, inflammatory disorders amenable to the invention encompass disorders associated with reactions of the specific defense system as well as with reactions of the nonspecific defense system.
  • the term “specific defense system” refers to the component of the immune system that reacts to the presence of specific antigens. Examples of inflammation resulting from a response of the specific defense system include the classical response to foreign antigens, autoimmune diseases, and delayed type hypersensitivity response mediated by T-cells. Chronic inflammatory diseases, the rejection of solid transplanted tissue and organs, e.g., kidney and bone marrow transplants, and graft versus host disease (GVHD), are further examples of inflammatory reactions of the specific defense system.
  • GVHD graft versus host disease
  • nonspecific defense system refers to inflammatory disorders that are mediated by leukocytes that are incapable of immunological memory (e.g., granulocytes, and macrophages).
  • inflammation that result, at least in part, from a reaction of the nonspecific defense system include inflammation associated with conditions such as adult (acute) respiratory distress syndrome (ARDS) or multiple organ injury syndromes; reperfusion injury; acute glomerulonephritis; reactive arthritis; dermatoses with acute inflammatory components; acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; thermal injury; inflammatory bowel disease; granulocyte transfusion associated syndromes; and cytokine-induced toxicity.
  • ARDS adult (acute) respiratory distress syndrome
  • multiple organ injury syndromes reperfusion injury
  • acute glomerulonephritis reactive arthritis
  • dermatoses with acute inflammatory components acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; thermal injury; inflammatory bowel disease; granulocyte transfusion associated syndromes; and
  • Autoimmune disease refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents.
  • Allergic disease refers to any symptoms, tissue damage, or loss of tissue function resulting from allergy.
  • Arthritic disease refers to any disease that is characterized by inflammatory lesions of the joints attributable to a variety of etiologies.
  • Dermatis refers to any of a large family of diseases of the skin that are characterized by inflammation of the skin attributable to a variety of etiologies.
  • Transplant rejection refers to any immune reaction directed against grafted tissue, such as organs or cells (e.g., bone marrow), characterized by a loss of function of the grafted and surrounding tissues, pain, swelling, leukocytosis, and thrombocytopenia.
  • the therapeutic methods of the present invention include methods for the treatment of disorders associated with inflammatory cell activation.
  • “Inflammatory cell activation” refers to the induction by a stimulus (including, but not limited to, cytokines, antigens, or auto-antibodies) of a proliferative cellular response, the production of soluble mediators (including but not limited to cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive amines), or cell surface expression of new or increased numbers of mediators (including, but not limited to, major histocompatability antigens or cell adhesion molecules) in inflammatory cells (including but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear leukocytes such as neutrophils, basophils, and eosinophils), mast cells, dendritic cells, Langerhans cells, and endothelial cells).
  • a stimulus including, but not limited to
  • TNF ⁇ tumor necrosis factor alpha
  • LPS lipopolysaccharide
  • superoxide release can be stimulated by formyl-Met-Leu-Phe (fMLP) or other peptides blocked at the N-terminus by formylated methionine.
  • fMLP formyl-Met-Leu-Phe
  • Such peptides normally are not found in eukaryotes, but are fundamentally characteristic of bacteria, and signal the presence of bacteria to the immune system.
  • Leukocytes expressing the fMLP receptor e.g., neutrophils and macrophages, are stimulated to migrate up gradients of these peptides (i.e., chemotaxis) toward loci of infection.
  • compounds of the present invention inhibit stimulated superoxide release by neutrophils in response to either TNF ⁇ or fMLP.
  • neutrophils Other functions of neutrophils, including stimulated exocytosis and directed chemotactic migration, also have been shown to be inhibited by the PI3K ⁇ inhibitors of the invention. Accordingly, compounds of the present invention can be expected to be useful in treating disorders, such as inflammatory disorders, that are mediated by any or all of these neutrophil functions.
  • the present invention enables methods of treating such diseases as arthritic diseases, such as rheumatoid arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis; Behcet disease; sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis, and toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage; ophthalmic disorders, such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated opthalmopathy; eosinophilic granuloma; pulmonary or respiratory disorders, such as asthma, chronic bronchitis, allergic rhinitis, ARDS, chronic pulmonary inflammatory disease (e.g., chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, emphyse
  • the method can have utility in treating subjects suffering from, or subject to, reperfusion injury, i.e., injury resulting from situations in which a tissue or organ experiences a period of ischemia followed by reperfusion.
  • ischemia refers to localized tissue anemia due to obstruction of the inflow of arterial blood.
  • Transient ischemia followed by reperfusion characteristically results in neutrophil activation and transmigration through the endothelium of the blood vessels in the affected area. Accumulation of activated neutrophils in turn results in generation of reactive oxygen metabolites, which damage components of the involved tissue or organ.
  • reperfusion injury is commonly associated with conditions such as vascular stroke (including global and focal ischemia), hemorrhagic shock, myocardial ischemia or infarction, organ transplantation, and cerebral vasospasm.
  • vascular stroke including global and focal ischemia
  • hemorrhagic shock myocardial ischemia or infarction
  • organ transplantation organ transplantation
  • cerebral vasospasm cerebral vasospasm.
  • reperfusion injury occurs at the termination of cardiac bypass procedures or during cardiac arrest when the heart, once prevented from receiving blood, begins to reperfuse. It is expected that inhibition of PI3K ⁇ activity will result in reduced amounts of reperfusion injury in such situations.
  • ischemia occurs when blood flow to the entire brain ceases for a period.
  • Global ischemia can result from cardiac arrest.
  • Focal ischemia occurs when a portion of the brain is deprived of its normal blood supply.
  • Focal ischemia can result from thromboembolytic occlusion of a cerebral vessel, traumatic head injury, edema, or brain tumor. Even if transient, both global and focal ischemia can cause widespread neuronal damage.
  • nerve tissue damage occurs over hours or even days following the onset of ischemia, some permanent nerve tissue damage can develop in the initial minutes following the cessation of blood flow to the brain.
  • Ischemia also can occur in the heart in myocardial infarction and other cardiovascular disorders in which the coronary arteries have been obstructed as a result of atherosclerosis, thrombus, or spasm. Accordingly, the invention is believed to be useful for treating cardiac tissue damage, particularly damage resulting from cardiac ischemia or caused by reperfusion injury in mammals.
  • selective PI3K ⁇ inhibitors of the present invention can be employed in methods of treating diseases of bone, especially diseases in which osteoclast function is abnormal or undesirable.
  • compounds of the present invention inhibit osteoclast function in vitro. Accordingly, the use of such compounds and other PI3K ⁇ selective inhibitors can be of value in treating osteoporosis, Paget's disease, and related bone resorption disorders.
  • the present invention includes methods of using PI3K ⁇ inhibitory compounds to inhibit the growth or proliferation of cancer cells of hematopoietic origin, preferably cancer cells of lymphoid origin, and more preferably cancer cells related to or derived from B lymphocytes or B lymphocyte progenitors.
  • lymphomas e.g., malignant neoplasms of lymphoid and reticuloendothelial tissues, such as Burkitt's lymphoma, Hodgkins' lymphoma, non-Hodgkins lymphomas, lymphocytic lymphomas and the like; multiple myelomas; leukemias, such as lymphocytic leukemias, chronic myeloid (myelogenous) leukemias, and the like.
  • the present PI3K ⁇ inhibitory compounds can be used to inhibit or control the growth or proliferation of chronic myeloid (myelogenous) leukemia cells.
  • cancer cells of hematopoietic origin or otherwise, that express p110 ⁇ also can be treated by administration of a PI3K ⁇ inhibitor of the present invention (C. Sawyer et al., Cancer Research, 63(7), 1667-75 (2003)).
  • the invention includes a method of suppressing a function of basophils and/or mast cells, thereby enabling treatment of diseases or disorders characterized by excessive or undesirable basophil and/or mast cell activity.
  • a present compound can be used to selectively inhibit the expression or activity of PI3K ⁇ in the basophils and/or mast cells.
  • the method employs a PI3K ⁇ inhibitor in an amount sufficient to inhibit stimulated histamine release by the basophils and/or mast cells.
  • a present selective PI3K ⁇ inhibitors can be of value in treating diseases characterized by histamine release, i.e., allergic disorders, including disorders such as chronic obstructive pulmonary disease (COPD), asthma, ARDS, emphysema, and related disorders.
  • allergic disorders including disorders such as chronic obstructive pulmonary disease (COPD), asthma, ARDS, emphysema, and related disorders.
  • COPD chronic obstructive pulmonary disease
  • asthma asthma
  • ARDS emphysema
  • emphysema emphysema
  • a compound of the present invention can be administered as the neat chemical, but it is typical, and preferable, to administer the compound in the form of a pharmaceutical composition or formulation.
  • the present invention also provides pharmaceutical compositions that comprise a present modulator of PI3K ⁇ activity and a biocompatible pharmaceutical carrier, adjuvant, or vehicle.
  • the composition can include the PI3K ⁇ activity modulation either as the sole active agent or in combination with other agents, such as oligo- or polynucleotides, oligo- or polypeptides, drugs, or hormones mixed with an excipient or other pharmaceutically acceptable carriers. Carriers and other ingredients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the present invention can be manufactured using any conventional method, e.g., mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes.
  • An optimal pharmaceutical formulation can be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent.
  • these pharmaceutical compositions can be formulated and administered systemically or locally.
  • compositions are formulated to contain suitable pharmaceutically acceptable carriers, and optionally can comprise excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the mode of administration generally determines the nature of the carrier.
  • formulations for parenteral administration can comprise aqueous solutions of the active compounds in water-soluble form.
  • Carriers suitable for parenteral administration can be selected from among saline, buffered saline, dextrose, water, and other physiologically compatible solutions.
  • Preferred carriers for parenteral administration are physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiologically buffered saline.
  • penetrants appropriate to the particular barrier to be permeated are used in the formulation.
  • the formulation can include stabilizing materials, such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
  • stabilizing materials such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
  • formulations for parenteral use can comprise dispersions or suspensions of the active compounds prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, dextran, and mixtures thereof.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent also can be used as coatings or matrix structures, e.g., methacrylic polymers, such as the EUDRAGIT® series available from Röhm America Inc. (Piscataway, N.J.).
  • Emulsions e.g., oil-in-water and water-in-oil dispersions, also can be used, optionally stabilized by an emulsifying agent or dispersant (surface active materials; surfactants).
  • Suspensions can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethlyene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethlyene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
  • Liposomes containing the active agent also can be employed for parenteral administration.
  • Liposomes generally are derived from phospholipids or other lipid substances.
  • the compositions in liposome form also can contain other ingredients, such as stabilizers, preservatives, excipients, and the like.
  • Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott (Ed.), Methods in Cell Biology, Vol. XIV, p. 33, Academic Press, New York (1976).
  • compositions comprising the agent in dosages suitable for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art.
  • Preparations formulated for oral administration can be in the form of tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, or powders.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Oral formulations can employ liquid carriers similar in type to those described for parenteral use, e.g., buffered aqueous solutions, suspensions, and the like.
  • Preferred oral formulations include tablets, dragees, and gelatin capsules. These preparations can contain one or excipients, which include, without limitation:
  • diluents such as sugars, including lactose, dextrose, sucrose, mannitol, or sorbitol;
  • binders such as magnesium aluminum silicate, starch from corn, wheat, rice, potato, etc.
  • cellulose materials such as methylcellulose, hydroxypropylmethyl cellulose, and sodium carboxymethylcellulose, polyvinylpyrrolidone, gums, such as gum arabic and gum tragacanth, and proteins, such as gelatin and collagen;
  • disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or a salt thereof, such as sodium alginate, or effervescent compositions;
  • lubricants such as silica, talc, stearic acid or its magnesium or calcium salt, and polyethylene glycol;
  • colorants or pigments e.g., to identify the product or to characterize the quantity (dosage) of active compound
  • ingredients such as preservatives, stabilizers, swelling agents, emulsifying agents, solution promoters, salts for regulating osmotic pressure, and buffers.
  • Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
  • Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc.
  • the active compounds can be dissolved or suspended in suitable fluids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
  • Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • the pharmaceutical composition can be provided as a salt of the active agent. Salts are more soluble in aqueous or other protonic solvents than the corresponding free acid or base forms.
  • Pharmaceutically acceptable salts are well known in the art. Compounds that contain acidic moieties can form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include, for example, alkali metal (e.g., sodium or potassium) and alkaline earth (e.g., calcium or magnesium) cations.
  • compositions of structural formula (I) and (II) that contain basic moieties can form pharmaceutically acceptable acid addition salts with suitable acids.
  • suitable acids for example, Berge et al., J. Pharm. Sci., 66:1 (1977), describe pharmaceutically acceptable salts in detail.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
  • Pharmaceutically acceptable salts of compounds of the invention generally are preferred in the methods of the invention.
  • pharmaceutically acceptable salts refers to salts or zwitterionic forms of the compounds of structural formulae (I) or (II). Suitable pharmaceutically acceptable cations include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) cations.
  • alkali metal e.g., sodium or potassium
  • alkaline earth metal e.g., calcium or magnesium
  • the pharmaceutically acceptable salts of compounds of structural formulae (I) or (II) that contain a basic center are acid addition salts formed with pharmaceutically acceptable acids.
  • acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, malonic, and citric.
  • salts of compounds of the invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, malonate, fumarate, maleate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate,
  • available amino groups present in the compounds of the invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phnethyl bromides.
  • any reference to compounds of the present invention appearing herein is intended to include compounds of structural formulae (I) and (II), as well as pharmaceutically acceptable salts, solvates, quaternary derivatives, and prodrugs, thereof.
  • compositions comprising a compound of the invention formulated in a pharmaceutically acceptable carrier can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • an article of manufacture such as a container comprising a dosage form of a compound of the invention and a label containing instructions for use of the compound.
  • Kits also are contemplated.
  • a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition.
  • conditions indicated on the label can include treatment of inflammatory disorders, cancer, and the like.
  • compositions comprising an inhibitor of PI3K ⁇ activity can be administered to the subject by any conventional method, including parenteral and enteral techniques.
  • Parenteral administration modalities include those in which the composition is administered by a route other than through the gastrointestinal tract, for example, intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intraarticular, intrathecal, and intraventricular injections.
  • Enteral administration modalities include, for example, oral, buccal, sublingual, and rectal administration.
  • Transepithelial administration modalities include, for example, transmucosal administration and transdermal administration.
  • Transmucosal administration includes, for example, enteral administration as well as nasal, inhalation, and deep lung administration; vaginal administration; and buccal and sublingual administration.
  • Transdermal administration includes passive or active transdermal or transcutaneous modalities, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or ointments.
  • Parenteral administration also can be accomplished using a high-pressure technique, e.g., POWDERJECT®.
  • Surgical techniques include implantation of depot (reservoir) compositions, osmotic pumps, and the like.
  • a preferred route of administration for treatment of inflammation can be local or topical delivery for localized disorders such as arthritis, or systemic delivery for distributed disorders, e.g., intravenous delivery for reperfusion injury or for systemic conditions such as septicemia.
  • administration can be accomplished by inhalation or deep lung administration of sprays, aerosols, powders, and the like.
  • parenteral administration is typically preferred.
  • Formulations of the compounds to optimize them for biodistribution following parenteral administration would be desirable.
  • the PI3K ⁇ inhibitor compounds can be administered before, during, or after administration of chemotherapy, radiotherapy, and/or surgery.
  • the therapeutic index of the PI3K ⁇ inhibitor compounds can be enhanced by modifying or derivatizing the compounds for targeted delivery to cancer cells expressing a marker that identifies the cells as such.
  • the compounds can be linked to an antibody that recognizes a marker that is selective or specific for cancer cells, so that the compounds are brought into the vicinity of the cells to exert their effects locally, as previously described (see for example, Pietersz et al., Immunol. Rev., 129:57 (1992); Trail et al., Science, 261:212 (1993); and Rowlinson-Busza et al., Curr. Opin. Oncol., 4:1142 (1992)).
  • PI3K ⁇ inhibitor compounds and radioisotopes or chemotherapeutic agents can be conjugated to the same antitumor antibody.
  • the PI3K ⁇ inhibitors can be delivered by any suitable method. Focal administration can be desirable, such as by intraarticular injection. In some cases, it can be desirable to couple the compounds to a moiety that can target the compounds to bone.
  • a PI3K ⁇ inhibitor can be coupled to compounds with high affinity for hydroxyapatite, which is a major constituent of bone. This can be accomplished, for example, by adapting a tetracycline-coupling method developed for targeted delivery of estrogen to bone (Orme et al., Bioorg. Med. Chem. Lett., 4(11):1375-80 (1994)).
  • the agents used in the methods of the invention should readily penetrate the blood brain barrier when peripherally administered. Compounds that cannot penetrate the blood brain barrier, however, can still be effectively administered by an intravenous route.
  • the characteristics of the agent itself and the formulation of the agent can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent.
  • Such pharmacokinetic and pharmacodynamic information can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials.
  • a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range that modulates PI3K ⁇ expression or activity. As human studies are conducted further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the “therapeutic index,” which typically is expressed as the ratio LD 50 /ED 50 .
  • Compounds that exhibit large therapeutic indices, i.e., the toxic dose is substantially higher than the effective dose, are preferred.
  • the data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • any effective administration regimen regulating the timing and sequence of doses can be used.
  • Compounds and pharmaceutical compositions suitable for use in the present invention include those wherein the active ingredient is administered in an effective amount to achieve its intended purpose. More specifically, a “therapeutically effective amount” means an amount sufficient to modulate PI3K ⁇ expression or activity, and thereby treat an individual suffering an indication, or to alleviate the existing symptoms of the indication. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • Exemplary dosage levels for a human subject are of the order of from about 0.001 milligram of active agent per kilogram body weight (mg/kg) to about 1000 mg/kg.
  • dosage units of the active agent comprise from about 0.01 mg to about 1000 mg, preferably from about 0.1 mg to about 100 mg, depending upon the indication, route of administration, and severity of the condition, for example.
  • a suitable dose can be calculated according to body weight, body surface area, or organ size.
  • the final dosage regimen is determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the specific activity of the compound, the identity and severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.
  • the frequency of dosing depends on the pharmacokinetic parameters of the agent and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the agent.
  • Short-acting pharmaceutical compositions i.e., short half-life
  • Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks.
  • Pumps such as subcutaneous, intraperitoneal, or subdural pumps, can be used for continuous infusion.
  • PI3K heterodimeric complexes consisting of a p110 catalytic subunit and a p85 regulatory subunit were overexpressed using the BAC-TO-BAC® HT baculovirus expression system (GIBCO/BRL), and then purified for use in biochemical assays.
  • the four Class I PI 3-kinases were cloned into baculovirus vectors as follows:
  • p110 ⁇ A FLAG®-tagged version of human p110 ⁇ (SEQ ID NOS: 1 and 2) (see Chantry et al., J. Biol. Chem., 272: 19236-41 (1997)) was subcloned using standard recombinant DNA techniques into the BamH1-Xba1 site of the insect cell expression vector pFastbac HTb (Life Technologies, Gaithersburg, Md.), such that the clone was in frame with the His tag of the vector.
  • the FLAG® system is described in U.S. Pat. Nos. 4,703,004; 4,782,137; 4,851,341; and 5,011,912, and reagents are available from Eastman Kodak Co.
  • p110 ⁇ Similar to the method used for p110 ⁇ , described above, a FLAG®-tagged version of p110 ⁇ (see Volinia et al., Genomics, 24(3):427-77 (1994)) was subcloned in BamH1-HindIII sites of pFastbac HTb (Life Technologies) such that the clone was in frame with the His tag of the vector.
  • p110 ⁇ A p110 ⁇ (see Hu et al., Mol. Cell. Biol., 13:7677-88 (1993)) clone was amplified from the human MARATHON® Ready spleen cDNA library (Clontech, Palo Alto Calif.) according to the manufacturer's protocol using the following primers:
  • 5′ Primer (SEQ ID NO: 3) 5′-GATCGAATTCGGCGCCACCATGGACTACAAGGACGACGATGACAAGT GCTTCAGTTTCATAATGCCTCC-3′ 3′ Primer (SEQ ID NO: 4) 5′-GATCGCGGCCGCTTAAGATCTGTAGTCTTTCCGAACTGTGTG-3′
  • the 5′ primer was built to contain a FLAG® tag in frame with the p110 ⁇ sequence. After amplification, the FLAG®-p110 ⁇ sequence was subcloned using standard recombinant techniques into the EcoR1-Not1 sites of pFastbac HTa (Life Technologies), such that the clone was in frame with the His tag of the vector.
  • p110 ⁇ The p110 ⁇ cDNA (see Stoyanov et al., Science, 269:690-93 (1995)) was amplified from a human Marathon Ready spleen cDNA library (Clontech) according to the manufacturer's protocol using the following primers:
  • Recombinant baculoviruses containing the above clones were generated using manufacturer's recommended protocol (Life Technologies). Baculoviruses expressing His-tagged p110 ⁇ , p110 ⁇ , or p110 ⁇ catalytic subunit and p85 subunit were coinfected into Sf21 insect cells. To enrich the heterodimeric enzyme complex, an excess amount of baculovirus expressing p85 subunit was infected, and the His-tagged p110 catalytic subunit complexed with p85 was purified on nickel affinity column. Since p110 ⁇ does not associate with p85, Sf21 cells were infected with recombinant baculoviruses expressing His-tagged p110 ⁇ only. In an alternate approach, p101 can be cloned into baculovirus, to permit coexpression with its preferred binding partner p110 ⁇ .
  • the 72-hour post-infected Sf21 cells (3 liters) were harvested and homogenized in a hypotonic buffer (20 mM HEPES-KOH, pH 7.8, 5 mM KCl, complete protease inhibitor cocktail (Roche Biochemicals, Indianapolis, Ind.), using a Dounce homogenizer.
  • the homogenates were centrifuged at 1,000 ⁇ g for 15 min.
  • the supernatants were further centrifuged at 10,000 ⁇ g for 20 min, followed by ultracentrifugation at 100,000 ⁇ g for 60 min
  • the soluble fraction was immediately loaded onto 10 mL of HITRAP® nickel affinity column (Pharmacia, Piscataway.
  • Buffer A 50 mM HEPES-KOH, pH 7.8, 0.5 M NaCl, 10 mM imidazole.
  • Buffer A 50 mM HEPES-KOH, pH 7.8, 0.5 M NaCl, 10 mM imidazole.
  • the column was washed extensively with Buffer A, and eluted with a linear gradient of 10-500 mM imidazole. Free p85 subunit was removed from the column during the washing step and only the heterodimeric enzyme complex eluted at 250 mM imidazole. Aliquots of nickel fractions were analyzed by 10% SDS-polyacrylamide gel electrophoresis (SDS-PAGE), stained with SYPRO® Red (Molecular Probes.
  • PI3K ⁇ is expressed at significant levels in leukocytes, it is important to study the effects of the PI3K ⁇ -selective inhibitor on leukocyte functions. Accordingly, the effects of PI3K ⁇ inhibition in several types of leukocytes were examined. Neutrophils were examined to determine the effects that selective inhibition of PI3K ⁇ might elicit (Example 2, below). It surprisingly was found that selective inhibition of PI3K ⁇ activity appears to be significantly associated with inhibition of some but not all functions characteristic of activated neutrophils. In addition, the effects of PI3K ⁇ inhibition on B cell and T cell function also were tested (Examples 3-4, below). Moreover, as PI3K ⁇ also is expressed in osteoclasts, the effect of PI3K ⁇ inhibition on the function of these specialized cells was studied (Example 5, below).
  • PI3K ⁇ inhibitor of the invention on neutrophil functions such as superoxide generation, elastase exocytosis, chemotaxis, and bacterial killing can be tested.
  • Superoxide generation is one of the hallmarks of neutrophil activation.
  • a variety of activators potentiate superoxide generation by neutrophils.
  • the effect of a present PI3K ⁇ inhibitor on superoxide generation by three different agonists: TNF1 ⁇ , IgG, and fMLP, each representing separate classes of activator, is measured.
  • Superoxide generated by the neutrophils is measured by monitoring a change in absorbance upon reduction of cytochrome C by modification of the method described by Green et al., (pp. 14.5.1-14.5.11 in Supp. 12, Curr. Protocols Immunol. (Eds., Colligan et al.) (1994)), as follows. Individual wells of a 96-well plate are coated overnight at 4° C.
  • fMLP bacterial peptide formylated-Met-Leu-Phe
  • activated neutrophils In addition to superoxide generation, activated neutrophils also respond by releasing several proteases that are responsible for the destruction of tissues and cartilage during inflammation. As an indication of protease release, the effect of present compound on elastase exocytosis is measured. Elastase exocytosis is quantitated by modification of the procedure described by Ossanna et al. (J. Clin. Invest., 77:1939-51 (1986)), as follows.
  • Purified human neutrophils (0.2 ⁇ 10 6 ) (treated with either DMSO or a serial dilution of a present compound in DMSO) are stimulated with fMLP in PBS containing 0.01 mg/mL cytochalasin B, 1.0 ⁇ M sodium azide (NaN 3 ), 5 ⁇ g/mL L-methionine and 1 ⁇ M fMLP for 90 min at 37° C. in a 96-well plate.
  • Absorbance at 410 nm is monitored for 2 hr in a 96-well plate reader. To measure the relative amounts of elastase excytosed, all absorbance values are normalized to the values without any inhibitor.
  • PI3K ⁇ inhibitor compounds of the present invention inhibit fMLP-induced elastase exocytosis significantly, and do so in a dose-dependent fashion.
  • Neutrophils have the intrinsic capacity to migrate through tissues, and are one of the first cell types to arrive at the sites of inflammation or tissue injury.
  • the effect of the present compounds on neutrophil migration towards a concentration gradient of fMLP is measured.
  • 6-well plates are coated with recombinant ICAM-1/Fc fusion protein (Van der Vieren et al., Immunity, 3:683-90 (1995)) (25 ⁇ g/mL in bicarbonate buffer, pH 9.3) and left overnight at 4° C.
  • 1% agarose solution in RPMI-1640 with 0.5% bovine serum albumin (BSA), is added to wells with or without an inhibitor, and plates are placed into a refrigerator before punching holes in the gelled agarose to create plaques (1 central hole surrounded by 6 peripheral ones per well).
  • BSA bovine serum albumin
  • Human neutrophils are obtained as described above, and resuspended in RPMI medium supplemented with 0.5% BSA at 5 ⁇ 10 6 cells/mL. After combining equal volumes of neutrophil suspension and medium (either with DMSO or a serial dilution of the test compound in DMSO), neutrophils are aliquoted into the peripheral holes, while the central hole received fMLP (5 ⁇ M). Plates are incubated at 37° C. in the presence of 5% CO 2 for 4 hr, followed by termination of migration by the addition of 1% glutaraldehyde solution in D-PBS. After removing the agarose layer, wells are washed with distilled water and dried.
  • Migration index is defined as the area under a curve representing number of migrated neutrophils versus the net distance of migration per cell.
  • PI3K ⁇ inhibitor compounds of the present invention have an effect on neutrophil migration, inhibiting this activity in a dose-dependent manner.
  • PI3K ⁇ inhibitor compounds of the present invention affect certain neutrophil functions, whether the compounds affect neutrophil-mediated bacterial killing is of interest.
  • the effect of the compounds on neutrophil-mediated Staphylococcus aureus killing is studied according to the method described by Clark and Nauseef (pp. 7.23.4-7.23.6 in Vol. 2, Supp. 6, Curr. Protocols Immunol. (Eds., Colligan et al.) (1994)).
  • Purified human neutrophils (5 ⁇ 10 6 cells/mL) (treated with either DMSO or a serial dilution of present compound in DMSO) are mixed with autologous serum. Overnight-grown S.
  • aureus cells are washed, resuspended in HBSS, and added to the serum-opsonized neutrophils at a 10:1 ratio.
  • Neutrophils are allowed to internalize the bacteria by phagocytosis by incubation at 37° C. for 20 min
  • the noninternalized bacteria are killed by 10 units/mL lysostaphin at 37° C. for 5 min and the total mixture is rotated at 37° C.
  • Samples are withdrawn at various times for up to 90 min and the neutrophils are lysed by dilution in water. Viable bacteria are counted by plating appropriate dilutions on trypticase-soy-agar plate and counting the S. aureus colonies after overnight growth.
  • Neutrophil-mediated killing of S. aureus is similar in samples treated with DMSO (control) and with a present compound. Therefore, a PI3K ⁇ inhibitor does not significantly affect the ability of neutrophils to kill S. aureus, suggesting that PI3K ⁇ is not involved in this pathway of neutrophil function.
  • Heparinized blood (200 mL) from healthy volunteers is mixed with an equal volume of D-PBS, layered on 10 ⁇ 10 mL FICOLL-PAQUE® (Pharmacia), and centrifuged at 1600 rpm for 30 min at room temperature.
  • Peripheral blood mononuclear cells (PBMC) are collected from the FICOLL®/serum interface, overlayed on 10 mL fetal bovine serum (FBS) and centrifuged at 800 rpm for 10 min to remove platelets. After washing, cells are incubated with DYNAL® Antibody Mix (B cell kit) (Dynal Corp., Lake Success, N.Y.) for 20 min at 4-8° C.
  • PBL are mixed with anti-mouse IgG coated magnetic beads (Dynal) for 20 min at 4-8° C. with gentle shaking followed by elimination of labeled non-B cells on the magnetic bead separator. This procedure is repeated once more.
  • the B cells are resuspended in RPMI-1640 with 10% FBS, and kept on ice until further use.
  • B cells are aliquoted at 50-75 ⁇ 10 3 cells/well into 96-well plate with or without inhibitor, to which IL-2 (100 U/mL) and PANSORBIN® (Calbiochem) Staphylococcus aureus cells (1:90,000) were added. Part of the media is removed after 24-36 hr, and fresh media (with or without inhibitor) and IL-2 is added. Cultures are incubated at 37° C., in the presence of a CO 2 incubator for additional 7 days. Samples from each condition (in triplicate) are removed, and analyzed for IgG and IgM, as measured by ELISA.
  • IL-2 100 U/mL
  • PANSORBIN® Calbiochem Staphylococcus aureus cells
  • IMMULON® 4 96-well plates are coated (50 ⁇ L/well) with either 150 ng/mL donkey antihuman IgG (H+L) (Jackson ImmunoResearch, West Grove Pa.), or 2 ⁇ g/mL donkey antihuman IgG+IgM (H+L) (Jackson ImmunoResearch) in bicarbonate buffer, and left overnight at 4° C.
  • Compounds of the present invention inhibited antibody production.
  • B cells are stimulated using PANSORBIN®.
  • the effect compounds of the present invention on B cell proliferation response when they are stimulated through their cell surface IgM using anti-IgM antibody also was measured.
  • Murine splenocytes (Balb/c) are plated into 96-well microtiter plates at 2 ⁇ 10 5 cells per well in 10% FBS/RPMI. Appropriate dilutions of test inhibitor in complete medium are added to the cells and the plates are incubated for 30-60 minutes prior to the addition of stimulus. Following the preincubation with test inhibitor, an F(ab′) 2 preparation of goat antibody specific for the ⁇ -chain of mouse IgM is added to the wells at a final concentration of 25 ⁇ g/mL.
  • the plates are incubated at 37° C. for 3 days and 1 ⁇ Ci of [ 3 H]-thymidine is added to each well for the final four hours of culture.
  • the plates are harvested onto fiber filters, washed, and the incorporation of radiolabel is determined using a beta counter (Matrix 96, Packard Instrument Co., Downers Grove, Ill.) and expressed as counts per minute (CPM).
  • Compounds of the present invention inhibit anti-IgM-stimulated B cell proliferation in a dose-dependent manner. Because compounds of the present invention inhibit B cell proliferation, it is envisioned that these compounds and other PI3K ⁇ inhibitors could be used to suppress undesirable proliferation of B cells in clinical settings. For example, in B cell malignancy, B cells of various stages of differentiation show unregulated proliferation. Based on the results shown above, one can infer that PI3K ⁇ selective inhibitors could be used to control, limit, or inhibit growth of such cells.
  • T cell proliferation in response to costimulation of CD3+CD28 is measured.
  • T cells are purified from healthy human blood by negative selection using antibody coated magnetic beads according to the manufacturer's protocol (Dynal) and resuspended in RPMI.
  • the cells are treated with either DMSO or a serial dilution of a present compound in DMSO and plated at 1 ⁇ 10 5 cells/well on a 96-well plate precoated with goat antimouse IgG.
  • Mouse monoclonal anti-CD3 and anti-CD28 antibodies then are added to each well at 0.2 ng/mL and 0.2 ⁇ g/mL, respectively.
  • the plate is incubated at 37° C. for 24 hr and [ 3 H]-thymidine (1 ⁇ Ci/well) is added. After another 18-hr incubation, the cells are harvested with an automatic cell harvester, washed, and the incorporated radioactivity was quantified.
  • the present PI3K ⁇ inhibitor compounds inhibited anti-CD3- and anti-CD28-induced proliferation of T cells, an effect is not as strong as an effect on B cells or on some of the functions of neutrophils. Accordingly, the present compounds are not toxic to cells in general.
  • mouse bone marrow cells are isolated and differentiated to osteoclasts by treating the cells with Macrophage Colony Stimulating Factor ⁇ 1 (mCSF ⁇ 1 ) and Osteoprotegerin Ligand (OPGL) in serum-containing medium ( ⁇ MEM with 10% heat-inactivated FBS; Sigma) for 3 days. On day four, when the osteoclasts had developed, the medium is removed and cells are harvested.
  • mCSF ⁇ 1 Macrophage Colony Stimulating Factor ⁇ 1
  • OPGL Osteoprotegerin Ligand
  • the osteoclasts are plated on dentine slices at 10 5 cells/well in growth medium, i.e., ⁇ MEM containing 1% serum and 2% BSA with 55 ⁇ g/mL OPGL and 10 ng/mL mCSF ⁇ 1 .
  • growth medium i.e., ⁇ MEM containing 1% serum and 2% BSA with 55 ⁇ g/mL OPGL and 10 ng/mL mCSF ⁇ 1 .
  • the medium is changed to 1% serum and 1% BSA, with or without osteopontin (25 ⁇ g/mL) and the PI3K inhibitors (100 nM).
  • the medium is changed every 24 hours with fresh osteopontin and the inhibitors.
  • the medium is removed, and the dentine surfaces are washed with water to remove cell debris and stained with acid hematoxylin. Excess stain is washed and the pit depths are quantitated using confocal microscopy.
  • the present PI3-kinase inhibitors had an inhibitory effect on osteoclast function. Both the nonspecific inhibitors LY294002 and wortmannin inhibited osteoclast activity. However, the present PI3K ⁇ inhibitor compounds had a greater effect, and in some cases almost completely inhibited osteoclast activity.
  • PI3K ⁇ activity can be used to suppress release of histamine, which is one of the mediators of allergy. Since the activity of various PI 3-kinases are required for protein trafficking, secretion, and exocytosis in many cell types, the above suggests that histamine release by other cells, such as mast cells, also can be disrupted by PI 3-kinase delta-selective inhibitors.
  • Step A A solution of 6-nitro-benzoic acid in benzene was treated with thionyl chloride (2.5 eq) and stirred at reflux for 8 h. After evaporation, the residue was dissolved in chloroform and then treated with methanol. After stirring at reflux for 3 h, the mixture was evaporated to afford compound 3.
  • Step B A mixture of compound 3 (2 g), N-bromosuccinimide (1.93 g), and benzoyl peroxide (0.124 g) in carbon tetrachloride (30 mL) was stirred at reflux overnight. After cooling, solids were filtered off and the filtrate was concentrated to yield compound 4 as a crude, yellow oil.
  • Step C A mixture of compound 4 (3.5 g, crude material), morpholine (0.99 g), potassium carbonate (2.89 g), and potassium iodide (1.66 g) in DMF (22 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated to a residue. The crude material was purified by flash chromatography (silica gel, 30-50% ethyl acetate/hexanes) to yield compound 5 as a yellow solid.
  • Step D A solution of compound 5 (0.85 g) and NaOH (0.304 g) in a mixture of water (9 mL), methanol (5 mL), and THF (45 mL) was stirred at reflux for 24 h and concentrated to dryness. The residue was dissolved in water, and the solution was cooled to 0° C. and adjusted to pH 7 with 10% potassium hydrogen sulfate. The mixture was concentrated to dryness, the residue was treated with methanol, and filtered to remove solids. The filtrate was concentrated to yield compound 6 as a yellow solid.
  • Step E A solution of compound 6 (0.62 g, 2.3 mmol) in THF (50 mL) was treated with thionyl chloride (0.94 mL), stirred at room temperature for 4 h, and evaporated to dryness. The residue was dissolved in THF (50 mL) and treated with aniline (0.58 mL, 6.4 mmol) and diisopropylethylamine (1.12 mL, 6.4 mmol). The reaction mixture was stirred for 4 h, concentrated, dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL), dried with sodium sulfate, and concentrated. The crude residue of compound 7 then was purified by flash chromatography (5% methanol in dichloromethane).
  • Step A A 250 mL, one-neck, round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1-chloromethyl-3-nitrobenzene (10.0 g, 58.3 mmol), morpholine (15.0 g, 175 mmol) and toluene (75 mL), and the solution was heated at reflux for 2.5 h. The reaction mixture was allowed to cool to ambient temperature then washed with 1N aqueous sodium hydroxide (2 ⁇ 50 mL). The aqueous layer was extracted with ethyl acetate (3 ⁇ 50 mL), and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure to afford compound 9 as an off-white solid.
  • Step B A 250-mL, three-neck, round bottomed flask equipped with a mechanical stirrer and reflux condensor was charged with compound 9 (12.7 g, 57.4 mmol), iron powder (40.0 g, 71.7 mmol), 2N hydrochloric acid (20 mL) and ethanol (75 mL). The resulting suspension was heated at reflux for 2 h. After this time the mixture was allowed to cool and filtered through a pad of CELITE® 521. The filtrate was concentrated under reduced pressure, the residue diluted with water (100 mL) and basified with solid potassium carbonate to pH 10.
  • Intermediate compound 11 was prepared using the method described above with respect to intermediate compound 10, but 2-amino-6-bromopurine was used in place of 6-bromopurine. Intermediate compound 11 is shown below.
  • the compounds of the present invention can be prepared by the following methods. Additional compounds are prepared using one of the following methods and selecting appropriate starting materials and reagents. General procedures and specific procedures for synthesizing the present compounds also are set forth in U.S. Pat. No. 6,518,277, incorporated herein by reference.
  • Step A Thionyl chloride (14.5 mL, 198 mmol) was added to a solution of 2-amino-6-methylbenzoic acid (10.0 g, 66.1 mmol) in benzene (250 mL). The resulting suspension was heated to reflux and stirred overnight. After cooling, the reaction was concentrated in vacuo, and the resulting residue was dissolved in chloroform (300 mL). Aniline (15 mL, 165 mmol) was added, and the mixture heated to reflux. After three hours, the reaction was allowed to cool and the resulting suspension was filtered. The filtrate was subjected to flash chromatography, and the crude product recrystallized from isopropanol to provide compound 15 as a yellow crystalline solid.
  • Step B Compound 15 (1.20 g, 5.30 mmol) was combined with 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester (2.13 g, 6.36 mmol), dimethylaminopyridine (915 mg, 7.49 mmol), and diisopropylethylamine (1.10 mL, 6.36 mmol) in toluene (15 mL). The mixture was heated to 110° C. and stirred at that temperature for 22 hours. After cooling, the reaction was purified by flash chromatography to provide the quinazolinone (16) as a pale yellow solid. MS (ES): m/z 428 (M+H).
  • Step C A catalytic amount of 10% Pd/C was added to a solution of compound 16 (691 mg, 1.62 mmol) in ethanol (8 mL). The resulting mixture was placed under a hydrogen atmosphere (balloon pressure) and allowed to stir at ambient temperature overnight. The reaction was filtered, and the filtrate concentrated in vacuo. The resulting crude residue was purified by flash chromatography to afford the free amine, compound 17, as a pale yellow oil.
  • Step C (alternative procedure): Trifluoroacetic acid was added to a solution of the Boc-protected amine compound 16 in dichloromethane. The resulting solution was allowed to stir at ambient temperature until LCMS or TLC indicated complete consumption of starting material. The reaction was concentrated in vacuo, and the residue purified by flash chromatography to provide the free amine 17.
  • Step D Compound 17 (100 mg, 0.341 mmol) was combined with 6-bromo purine (75 mg, 0.375 mmol) and diisopropylethylamine (65 uL, 0.375 mmol) inn-butanol (1.0 mL). The reaction was sealed, heated to 120° C., and stirred for 18 hours. The solution was allowed to cool, then concentrated in vacuo. The resulting residue was purified by prep HPLC to provide compound 14 as an olive solid.
  • Compound 20 was prepared using the general procedure described above with respect to compound 14, but 2,6-difluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D.
  • ESI-MS m/z 449.5 (MH 30 ). Compound 20 is shown below.
  • Compound 21 was prepared using the general procedure described above with respect to compound 14, but 2,6-difluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 2-fluoro-6-chloropurine was substituted for 6-bromopurine in step D.
  • Compound 32 was prepared using the general procedure described above with respect to compound 14, but, with the following changes: 4-fluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the alternate procedure (TFA deprotection) was used in step C.
  • ESI-MS m/z 416.1 (MH + ). Compound 32 is shown below.
  • Compound 33 was prepared using the general procedure described above with respect to compound 14, but 4-fluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D.
  • ESI-MS m/z 431.1 (MH + ). Compound 33 is shown below.
  • Compound 34 was prepared using the general procedure described above with respect to compound 14, but, 4-fluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 2-fluoro-6-chloropurine was substituted for 6-bromopurine in step D.
  • ESI-MS m/z 434.1 (MH + ). Compound 34 is shown below.
  • Compound 37 was prepared using the general procedure described above with respect to compound 14, but 3-fluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the alternate procedure (TFA deprotection) was used in step C.
  • Compound 38 was prepared using the general procedure described above with respect to compound 14, but 3-fluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D.
  • Compound 48 was prepared using the general procedure described above with respect to compound 14, but 2-amino-6-chlorobenzoic acid was substituted for 2-amino-6-methylbenzoic acid in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D.
  • Compound 48 is shown below.
  • Compound 53 was prepared using the general procedure described above with respect to compound 14, but anthranilic acid was substituted for 2-amino-6-methylbenzoic acid in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the alternate procedure (TFA deprotection) was used in step C.
  • Compound 64 was prepared using the general procedure described above with respect to compound 14, but m-toluidine was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the alternate procedure (TFA deprotection) was used in step C.
  • Compound 65 was prepared using the general procedure described above with respect to compound 14, but m-toluidine was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D.
  • Compound 70 was prepared using the general procedure described above with respect to compound 14, but 2,6-difluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D.
  • ESI-MS m/z 435.1 (MH + ). Compound 70 is shown below.
  • 2-amino-N-phenyl-6-trifluoromethyl-benzamide was prepared by addition of aniline (1.0 eq.) to a suspension of 2-amino-6-(trifluoromethyl)-benzoic acid trihydrate (1.0 g, 4.0 mmol, 1.3 eq.) and polystyrene-carbodiimide (3.6 g, 1.1-1.7 eq.) in THF (40 mL). The reaction was stirred at ambient temperature for 18 hours, then filtered. The filtrate was concentrated in vacuo and purified by flash chromatography to provide 2-amino-N-phenyl-6-trifluoromethyl-benzamide as a yellow solid.
  • Compound 80 was prepared using the general procedure described above with respect to compound 14, but 2,6-dichloroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the alternate procedure (TFA deprotection) was used in step C. ESI-MS m/z 467 (MH + ). Compound 80 is shown below.
  • Compound 92 was prepared by adding trifluoroacetic acid to a solution of 2-[2-tert-butoxy-1-(9H-purin-6-ylamino)-ethyl]-3-phenyl-3H-quinazolin-4-one in dichloromethane. The reaction was stirred at ambient temperature for 18 hours, then concentrated in vacuo. Purification by LC provided the product as a white solid. MS (ES): m/z 400 (M+H), 382, 200, 136. Compound 92 is shown below.
  • Compound 95 was prepared using the general procedure described above with respect to compound 14, but anthranilic acid was substituted for 2-amino-6-methylbenzoic acid and 3,5-difluoroaniline for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the alternate procedure (TFA deprotection) was used in step C. ESI-MS m/z 420 (MH + ). Compound 95 is shown below.
  • Compound 100 was prepared using the general procedure described above with respect to compound 14, but anthranilic acid was substituted for 2-amino-6-methyl-benzoic acid in step A, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D.
  • Compound 100 is shown below.
  • Step A A 10-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 10% palladium on carbon (30 mg, 50% wet). A solution of [4-benzyloxycarbonylamino-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-butyl]-carbamic acid tert-butyl ester (product from step B of procedure for compound 51) (100 mg, 0.18 mmol) in ethanol (2 mL) and polymethylhydrosiloxane (130 mg) were then added sequentially. The reaction mixture was stirred at 50° C. for 3 h, and then cooled to room temperature.
  • Step B A 10-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen, and then charged with the compound 104 (100 mg, 0.24 mmol) and 1,2-dichloroethane (2 mL). Acetaldehyde (42 mg, 0.85 mmol) and sodium triacetoxyborohydride (400 mg, 1.90 mmol) were subsequently added. The reaction mixture was stirred for 18 h at ambient temperature, evaporated to dryness, and the resulting residue was dissolved in methanol (20 mL).
  • Step A A solution of 2-fluoro-6-nitrobenzoic acid (100 g, 0.54 mol) and dimethylformamide (5 mL) in dichloromethane (600 mL) was treated dropwise with oxalyl chloride (2 M in dichloromethane, 410 mL, 0.8 mol, 1.5 eq) over 30 min. After stirring 2 h at room temperature, the reaction was concentrated to an orange syrup with some solids present.
  • the syrup was dissolved in dry dioxane (80 mL) and slowly added to a suspension of aniline (49 mL, 0.54 mol, 1 eq) and sodium bicarbonate (90 g, 1.08 mol, 2 eq) in a mixture of dioxane (250 mL) and water (250 mL) at 6° C. The temperature reached 27° C. at the end of the addition. After 30 min, the reaction mixture was treated with water (1.2 L). The precipitate was collected by vacuum filtration, washed with water (300 mL), air dried in the funnel, and dried in vacuo at 50° C. for 24 h to afford an off-white solid product (139 g, 99%).
  • Step B A suspension of compound 108 (0.5 mol) and dimethylformamide (5 mL) in thionyl chloride (256 mL, 2.5 mol, 5 eq) was stirred at 85° C. for 5 hours. The reaction mixture was concentrated in vacuo to a brown syrup. The syrup was dissolved in dichloromethane (200 mL) and was slowly added to a solution of N—BOC-L-2-aminobutyric acid (112 g, 0.55 mol, 1.1 eq) and triethylamine (77 mL, 0.55 mol, 1.1 eq) in dichloromethane (600 mL) at 10° C.
  • Step C A solution of compound 109 (125 mmol, 1 eq) in acetic acid (500 mL) was treated with zinc dust (48.4 g, 740 mmol, 6 eq) added in 3 portions, and the reaction mixture was allowed to cool to below 35° C. between additions. After stirring for 2 h at ambient temperature, solids were filtered off by vacuum filtration and washed with acetic acid (50 mL). The filtrate was concentrated in vacuo, dissolved in EtOAc (400 mL), washed with water (300 mL), and the water layer was extracted with EtOAc (300 mL).
  • Step D A solution of compound 110 (85 mmol) in dichloromethane (60 mL) was treated with trifluoroacetic acid (60 mL). The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between dichloromethane (150 mL) and 10% K 2 CO 3 (sufficient amount to keep the pH greater than 10). The aqueous layer was extracted with additional dichloromethane (100 mL), and the combined organic layers were washed with water (50 mL) and brine (50 mL). After drying with Mg SO 4 , the solution was concentrated to provide compound III as an off-white solid (22 g, 88%).
  • Step E A suspension of compound 111 (65.6 mmol, 1 eq), 6-bromopurine (14.6 g, 73.4 mmol, 1.1 eq), and DIEA (24.3 mL, 140 mmol, 2 eq) in tert-butanol (40 mL) was stirred for 24 h at 80° C. The reaction mixture was concentrated in vacuo and treated with water to yield a solid crude product that was collected by vacuum filtration, washed with water, and air dried.
  • Compound 118 was prepared using an alternative step B relative to the preparation of compound 107, but the general procedure described above for compound 107 was otherwise generally followed for each of steps A, C, and D.
  • Step A Compound 118a was prepared following the preparation procedure described above with respect to compound 107, but 2-nitro-5-methylbenzoic acid was substituted for 2-fluoro-6-nitrobenzoic acid and 2,6-difluoroaniline was substituted for aniline.
  • Step B Compound 118b was prepared by treating a solution of compound 118a (13.8 g, 47 mmol) in THF (200 mL) dropwise with a solution of potassium hexamethyldisilazide (KHMDS) (0.5 M in toluene, 95 mL, 47 mmol, 1 eq) at 0° C. and stirring the reaction mixture for 30 min at the same temperature. The reaction mixture was then treated with L-2-tert-butoxycarbonylamino-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester (13.5 g, 47 mmol, 1 eq) and stirred at the same temperature for an additional 30 min.
  • KHMDS potassium hexamethyldisilazide
  • the reaction mixture was quenched with water (50 mL) and concentrated in vacuo.
  • the residue was dissolved in ethyl acetate (300 mL), and washed with 100 mL of each of the following: (1) water, (2) sat'd sodium bicarbonate, (3) water, (4) 5% citric acid, (5) water, and (6) brine.
  • the organic layer was dried with MgSO 4 and concentrated to a syrup.
  • the crude material was dissolved in dichloromethane (75 mL) and purified by flash chromatography on silica gel (7.5 ⁇ 40 cm), eluted with 20% EtOAc in hexanes (10 L of 20%, then 6 L of 33%).
  • Compound 120 was prepared using the general procedure described above with respect to compound 107, but 2-methyl-6-nitro-benzoic acid was substituted for 2-fluoro-6-nitrobenzoic acid in step A and 2-tert-butoxycarbonylamino-4,4,4-trifluoro-butyric acid was substituted for 2-tert-butoxycarbonylamino-butyric acid in step B.
  • ESI-MS m/z 466 (MH + ). Compound 120 is shown below.
  • Step A A 5-L, three-neck, round bottomed flask equipped with a gas bubbler, mechanical stirrer and reflux condenser was charged with 6-amino-2-methylbenzoic acid (25 g, 16.8 mmol), toluene (300 mL), and thionyl chloride (50 mL). The reaction mixture was refluxed for 1 h until evolution of gas ceased. The resulting mixture was then cooled and concentrated under reduced pressure at 50° C. Anhydrous THF (400 mL) and DIEA (90 mL) were added to the resulting residue, followed by compound 122 (37 g, 1.0 eq).
  • Step B A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and a reflux condenser was purged with nitrogen and charged with compound 123 (10 g, 28 mmol), N-tert-butyloxycarbonylalanine N-hydroxysuccinimide ester (9.60 g, 1.0 eq), DMAP (1.90 g), DIEA (6 mL), 4 ⁇ molecular sieves (1.20 g), and anhydrous toluene (100 mL). The resulting mixture was heated in an oil bath at 80° C. for 24 h. 1-Hydroxybenzotriazole (3.78 g) was added to the reaction, and heating continued for an additional 48 h.
  • Step C1 A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer was charged with compound 124 (4.50 g, 11.18 mmol) in CH2Cl2 (15 mL) and TFA (15 mL). After stirring for 1 hr at room temperature, the mixture was concentrated under reduced pressure to afford compound 125, which was used as is in the following step.
  • Step C2 A nitrogen purged, 50-mL one-neck round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with compound 125 (2.4 g, 8.16 mmol), intermediate compound 10 (2.70 g, 1.0 eq), n-butanol (20 mL), and DIEA (4.2 mL). The mixture was heated at 100° C. for 4 h then cooled to room temperature. Concentration of the reaction mixture under high vacuum followed by column chromatography gave compound as a white solid. The preparation of compound 126 is generally shown above as step C of Procedure C.
  • Step A A nitrogen purged, 50-mL one-neck round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with compound 125 (3.02 g, 10.2 mmol), intermediate compound 12 (5.56 g, 1.0 eq), n-butanol (20 mL), and DIPEA (6.0 mL). The mixture was heated at 100° C. for 1 h, and then cooled to room temperature. Concentration of the reaction mixture under high vacuum followed by column chromatography gave compound 133 as a white solid.
  • Step A A 50-mL, three-neck, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with compound 126 (500 mg, 0.92 mmol), triethylamine (218 mg, 2.16 mmol), anhydrous methylene chloride (10 mL) and N-phenyltrifluoromethanesulfonimide (496 mg, 1.39 mmol). After stirring for 2 h at ambient temperature, the reaction mixture was partitioned between methylene chloride (50 mL) and 10% aqueous potassium carbonate (50 mL). The organic phase was separated, dried over sodium sulfate and filtered.
  • Step B A 5-mL reaction vial equipped with a magnetic stirrer was purged with nitrogen and charged with compound 138 (220 mg, 0.33 mmol), dichlorobis(triphenylphosphine) palladium(II) (27.1 mg, 0.039 mmol), and anhydrous DMF (1 mL). Triethylamine (146 mg, 1.44 mmol) and (trimethylsilyl) acetylene (102 mg, 1.04 mmol) were added, and the reaction mixture was stirred for 10 h at 90° C. and an additional 8 h at 100° C. Evaporation of the reaction mixture to dryness followed by column chromatography purification afforded 63% yield of compound 139 as an off-white solid.
  • Compound 140 was prepared according to the procedures set forth in steps A and B below.
  • Step A A 5-mL reaction vial equipped with a magnetic stirrer was charged with compound 138 (200 mg, 0.300 mmol), tetrakis(triphenylphosphine)palladium (34.0 mg, 0.029 mmol), zinc cyanide (70 mg, 0.60 mmol) and anhydrous DMF (1 mL). The vial was purged with nitrogen, heated to 120° C. for 3.5 h then cooled to ambient temperature and poured into a saturated aqueous sodium bicarbonate solution (25 mL). The resulting suspension was extracted with methylene chloride (3 ⁇ 20 mL), and the organic extracts were combined, dried over sodium sulfate and filtered.
  • Step A A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and a reflux condenser was purged with nitrogen and charged with compound 141 (219 mg, 0.40 mmol) and anhydrous methylene chloride (15 mL). N,N-Diethylhydroxylamine (146 mg, 1.64 mmol) was added to the resulting solution, and the reaction mixture was heated for 16 h at 50° C., cooled to ambient temperature, and then evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography to give a 97% yield of compound 143 as a white solid. m.p.
  • Step A Compound 149 was obtained from 6-amino 3-fluoro benzoic acid using the procedures described above for compounds 123, 124, 125, and 126.
  • Step A Compound 152 was obtained from compound 133, which was reacted in accordance with the procedure described for compound 138.
  • Step A A 3-mL reaction vial was charged with compound 138 (96.1 mg, 0.142 mmol), palladium(II) acetate (3.20 mg, 0.014 mmol), cesium carbonate (84.2 mg, 0.258 mmol) and (+)-BINAP (i.e., 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (13.8 mg, 0.022 mmol). The vial was then flushed with nitrogen for 10 min. Toluene (0.3 mL) and morpholine (18 ⁇ L) were then added, and the solution was heated at 100° C. for 6 h.
  • compound 138 96.1 mg, 0.142 mmol
  • palladium(II) acetate 3.20 mg, 0.014 mmol
  • cesium carbonate 84.2 mg, 0.258 mmol
  • (+)-BINAP i.e., 2,2′-bis(diphenylphosphino)-1,1′
  • Procedure E provides an additional alternative method of preparing compounds with a variety of side chains appended to the linker between the quinazolinone and purine rings of the inventive compounds. Although a propargyl functional group is exemplified, the method illustrated in Procedure E is applicable to many known functional groups.
  • Compound 161 was prepared according to the procedures set forth in steps A-D below.
  • Step A A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-aminomethyl-5-methyl-3-phenyl-3H-quinazolin-4-one (2.91 g, 11.0 mmol), benzhydrylideneamine (2.39 g, 13.2 mmol), and 1,2-dichloroethane (15 mL). The reaction mixture was heated at reflux for 4 h under nitrogen atmosphere and then cooled to ambient temperature. Concentration under reduced pressure followed by purification by column chromatography afforded the compound 162 as an orange solid. m.p. 49° C.
  • Step B A 25-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with compound 162 (500 mg, 1.20 mmol) and anhydrous THF (4 mL). A 1M solution of potassium tert-butoxide in THF (1.40 mL, 1.40 mmol) was added in one portion. After stirring for 20 min at ambient temperature, an 80% solution of propargyl bromide in toluene (210 ⁇ L, 1.89 mmol) was added, and the reaction stirred for an additional 15 min at ambient temperature.
  • Step C A 50-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was charged with compound 163 (193 mg, 0.41 mmol) and diethyl ether (5 mL). A 2N solution of hydrochloric acid (5 mL) was added in one portion. After stirring for 1.5 h at ambient temperature, sodium chloride (750 mg, 12.8 mmol) was added to the reaction mixture, and stirring was continued for an additional 10 min. The resulting precipitate was filtered, washed sequentially with diethyl ether (0.5 mL), 2N hydrochloric acid (1 mL), and MtBE (2 ⁇ 1 mL). Drying under vacuum at 45° C. for 2 h afforded the product as a pink solid.
  • Step D Compound 161 was prepared by reacting compound 164 prepared following the procedure for the preparation of compound 14 (step D) using three equivalents of diisopropylethylamine instead of one.
  • ESI-MS m/z 422 (MH + ). The reaction described above and compound 161 are shown below.
  • Compound 165 was prepared following the general procedure described above for the preparation of compound 161, but 2-amino-6-bromopurine was substituted for 6-bromopurine in step D.
  • ESI-MS m/z 437 (MH + ).
  • Procedure K provides an additional alternative method of preparing such compounds via an oxazine intermediate (step C).
  • Step A Compound 167 was prepared following the procedure following the procedure for the preparation of compound 15 (step A), but 2-amino-6-chlorobenzoic acid was substituted for 2-amino-6-methylbenzoic acid and 3,5-difluoroaniline was substituted for aniline. The reaction described above and compound 167 are shown below.
  • Step B A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with the compound 167 (10.6 mmol), N-tert-butyloxycarbonyl-D,L-alanine N-hydroxysuccinimide ester (3.64 g, 12.7 mmol), 4-N,N-dimethylaminopyridine (710 mg, 5.82 mmol) and 4 ⁇ molecular sieves (3.00 g). The flask was purged with nitrogen, and anhydrous toluene (15 mL) and N,N-diisopropylethylamine (1.64 g, 2.22 mmol) were added.
  • Step C A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and thermometer was purged with nitrogen and charged with compound 168 (3.30 mmol), anhydrous methylene chloride (25 mL), N,N-diisopropylethylamine (4.60 g, 35.7 mmol) and triphenylphosphine (3.98 g, 15.2 mmol).
  • the reaction mixture was then cooled to 0-5° C. in an ice/water bath. Iodine (3.61 g, 14.2 mmol) was then added portion-wise to the reaction mixture over 1 h. Once the addition was complete, the cooling bath was removed, and the mixture was stirred at room temperature for an additional 30 min.
  • Step D A solution of compound 169 (1.68 mmol) in piperidine (2 mL) was stirred for 3 h at ambient temperature. Evaporation of the reaction mixture to dryness under high vacuum gave a yellow foam. This foam was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 17 h at ambient temperature. The reaction mixture was then concentrated to dryness, basified with 10% aqueous potassium carbonate (40 ml) and extracted with MTBE (3 ⁇ 20 mL). Combining the organic extracts, drying over sodium sulfate and concentrating to dryness afforded a solid residue.
  • Step E Compound 166 was prepared by reacting compound 170 in according to the procedure for the preparation of compound 107 (final procedure). ESI-MS m/z 454.3 (MH + ). The reaction described above and compound 166 are shown below.
  • Compound 171 was prepared following the general procedure for compound 161 (steps A-E), but 2-tert-butoxycarbonylamino-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester was substituted for N-tert-butyloxycarbonyl-D,L-alanine N-hydroxysuccinimide ester in step B, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step E.
  • ESI-MS m/z 454.3 (MH + ).
  • the structure of compound 171 is shown below.
  • Compound 172 was prepared following the general procedure for compound 161 (steps A-E), but 2-amino-6-bromopurine was substituted for 6-bromopurine in step E.
  • the structure of compound 172 is shown below.
  • Compound 175 was prepared following the general procedure for compound 161 (steps A-E), but 2,6-difluoroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester was substituted for N-tert-butyloxycarbonyl-D,L-alanine N-hydroxysuccinimide ester in step B, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step E.
  • ESI-MS m/z 483.2 (MH + ). The structure of compound 175 is shown below.
  • Step A (S)-2-Acetoxypropionyl chloride (5.469 g, 36.32 mmol) was added to a solution of compound 15 (6.788 g, 30 mmol) in dichloromethane (150 mL). A precipitate immediately formed. The reaction was stirred for 25 h and the precipitate was filtered off. The filtrate was washed with saturated sodium bicarbonate solution (3 ⁇ 50 mL) and dried (MgSO 4 ). Filtration and concentration of the filtrate gave a brown solid (7.6 g).
  • Step B Compound 177 (0.34 g, 1.0 mmol) was dissolved in dichloromethane (25 mL). Triphenylphosphine (1.311 g, 5 mmol) was added to the solution, followed by iodine (1.269 g, 5 mmol) and DIEA (1.9 mL, 11 mmol). The reaction was capped and stirred for 4 days. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (25 mL). The organic layer was separated, dried (MgSO 4 ), filtered, and the filtrate concentrated under reduced pressure to give a dark brown gum (2.886 g).
  • Step F A solution of compound 181 (0.069 g, 0.25 mmol) in THF (5 mL) was treated with sodium hydride (0.007 g, 0.27 mmol) and stirred for 10 min.
  • the flask originally containing the intermediate compound 13 was washed with additional THF (1 mL) and the washings were also added to the reaction mixture.
  • the reaction was allowed to proceed, and additional sodium hydride (0.005 g, 0.21 mmol) was added at 21.5 h and 23 h.
  • the reaction was quenched after a total of 24 h by addition of saturated ammonium chloride solution (5 mL).
  • IC 50 values are given for PI3K ⁇ (“Delta”), and may be calculated for the other isoforms using the ratios of IC 50 values discussed below.
  • the ratios of the IC 50 values of the compounds for PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ relative to PI3K ⁇ are given, respectively, as “Alpha/Delta Ratio,” “Beta/Delta Ratio,” and “Gamma/Delta Ratio.”
  • the initial selectivity assays were performed identically to the selectivity assay protocol in Example 2, except using 100 ⁇ L Ecoscint for radiolabel detection. Subsequent selectivity assays were done similarly using the same 3 ⁇ substrate stocks except they contained 0.05 mCi/mL ⁇ [ 32 P]ATP and 3 mM PIP2. Subsequent selectivity assays also used the same 3 ⁇ enzyme stocks, except they now contained 3 nM of any given PI3K isoform.
  • test compounds were weighed out and dissolved into 10-50 mM stocks in 100% DMSO (depending on their respective solubilities) and stored at ⁇ 20° C. Compounds were thawed (to room temperature or 37° C.), diluted to 300 ⁇ M in water from which a 3-fold dilution series into water was done. From these dilutions, 20 ⁇ L was added into the assay wells alongside water blanks used for the enzyme (positive) control and the no enzyme (background) control. The remainder of the assay was performed essentially according to the selectivity assay protocol in Example 2.

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US14/826,096 Active US10336756B2 (en) 2004-05-13 2015-08-13 (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one precursor of a quinazolinone as inhibitor of human phosphatidylinositol 3-kinase delta
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LUC00005I1 (fr) 2017-02-21
US9149477B2 (en) 2015-10-06
EP2612862B1 (fr) 2016-09-14
ES2873875T3 (es) 2021-11-04
HRP20161751T1 (hr) 2017-04-07
PT2612862T (pt) 2016-12-15
WO2005113554A2 (fr) 2005-12-01
HUE030950T2 (en) 2017-06-28
US8207153B2 (en) 2012-06-26
US20100256167A1 (en) 2010-10-07
PL3153514T3 (pl) 2022-01-10
US8586597B2 (en) 2013-11-19
EP1761540B1 (fr) 2016-09-28
LUC00005I2 (fr) 2017-05-02
US20100256168A1 (en) 2010-10-07
HUE030839T2 (en) 2017-06-28
US20140121223A1 (en) 2014-05-01
LT1761540T (lt) 2017-02-27
US10906907B2 (en) 2021-02-02
LTC1761540I2 (lt) 2019-04-10
US7932260B2 (en) 2011-04-26
CN102229609A (zh) 2011-11-02
PT3153514T (pt) 2021-06-25
RS55551B1 (sr) 2017-05-31
US20140121224A1 (en) 2014-05-01
US8980901B2 (en) 2015-03-17
IL179176A0 (en) 2007-03-08
US20130231356A1 (en) 2013-09-05
CN101031569A (zh) 2007-09-05
ME02688B (me) 2017-10-20
EP3153514A1 (fr) 2017-04-12
EP2612862A3 (fr) 2014-01-08
PL1761540T3 (pl) 2017-06-30
HUS1700006I1 (hu) 2017-03-28
IL241732B (en) 2019-10-31
CA2566609A1 (fr) 2005-12-01
DK1761540T3 (en) 2016-11-21
NL300867I2 (fr) 2017-05-09
IL269976B (en) 2021-04-29
AU2005245875A1 (en) 2005-12-01
US10336756B2 (en) 2019-07-02
US20210332047A1 (en) 2021-10-28
EP2612862A2 (fr) 2013-07-10
SI2612862T1 (sl) 2017-04-26
US20160075705A1 (en) 2016-03-17
EP1761540A1 (fr) 2007-03-14
CY1118493T1 (el) 2017-07-12
AU2005245875B2 (en) 2009-07-30
US20130116266A1 (en) 2013-05-09
US8993583B2 (en) 2015-03-31
CY1118516T1 (el) 2017-07-12
WO2005113554A3 (fr) 2006-04-06
AU2005245875C1 (en) 2017-08-31
JP2007537291A (ja) 2007-12-20
EP3153514B1 (fr) 2021-04-21
RS55546B1 (sr) 2017-05-31
ES2605792T3 (es) 2017-03-16
BE2017C002I2 (fr) 2024-08-08
EP3943494A1 (fr) 2022-01-26
US20200017503A1 (en) 2020-01-16
PT1761540T (pt) 2016-12-07

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